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This issue features 12 papers on cryo-electron microscopy (cryo-EM), GlyT2 transport and analgesia, and related biomedical mechanisms. Cryo-EM studies cover post-acquisition super-resolution, ultrasound-assisted improvements in particle orientation, deep learning–based map post-processing, and validation of continuous conformational changes using real particle data. GlyT2 studies reveal ion-coupled transport mechanisms and how several classes of inhibitors act, with reversible allosteric inhibitors showing analgesic potential in mice. Other studies examine transport across the Mycobacterium tuberculosis cell wall, tianeptine’s regulation of synaptic AMPA receptors, SLC25A34’s coordination of lipid cycling, and RNA-binding proteins as potential drug targets. Together, these papers highlight the complementary value of structural and functional evidence. Preprints, animal findings, and promising targets do not, on their own, establish clinical efficacy or safety.
This issue features 12 papers covering cryo-EM sample preparation and data processing, GlyT2 transport and analgesia, synaptic signaling, lipid metabolism, and RNA-binding proteins as drug targets.
Cryo-EM Sample Preparation and Data Processing (4 papers)
01 · Post-acquisition super resolution for cryo-electron microscopy
IUCrJ · Publication/issue date: 2026-09-01
Authors: R. N. Burton Smith, K. Murata
When a cryo-EM reconstruction approaches the Nyquist limit imposed by pixel sampling, further improvements in resolution usually require changes to acquisition conditions. This study introduces post-acquisition super resolution (PASR), which doubles the pixel sampling of raw counting-mode movies before motion correction, potentially allowing reconstructions from existing data to exceed the physical sampling limit. The authors tested the approach on samples of various sizes and symmetries and report that it can also be applied to data acquired in super-resolution mode. The method may reduce the magnification needed to reach a target resolution, improving acquisition efficiency. A key prerequisite, however, is that the raw data already reach the relevant Nyquist limit: doubling the pixel sampling does not create genuine structural information out of nothing in an arbitrary dataset.
Highlight · PASR offers a post-processing route to extract more structural information from movie data that have already reached their sampling limit.
02 · Plunge freezing tweezers with ultrasonic excitation for reducing preferred particle orientation in cryo-EM
Preprint · Publication/issue date: 2026-10-04
Authors: Jakub Wenz, Mischa Flór, Constantin R. Krüger, Marcel Drabbels, Ulrich J. Lorenz
Particle adsorption at the air–water interface can cause preferred orientation, leaving some views heavily overrepresented and others entirely absent. This preprint integrates an ultrasonic transducer into the sample-holding plunge-freezing tweezers to excite the sample during vitrification and improve its angular distribution. The authors previously proposed detaching particles from the air–water interface so that their orientations could redistribute; this work focuses on an implementation compatible with plunge-freezing equipment. In tests with hemagglutinin, which is prone to preferred orientation, the proportion of side and tilted views increased with excitation amplitude, ultimately yielding a complete trimer reconstruction at 2.5 Å. The results show that active perturbation during sample preparation can improve orientation coverage, but the demonstrated benefits come from a specific test system and require evaluation in other samples.
Highlight · Integrating ultrasonic excitation into plunge-freezing tweezers can improve particle view coverage during sample preparation.
Authors: Ruben Sanchez-Garcia, Josue Gomez-Blanco, Ana Cuervo, Jose Maria Carazo, Carlos Oscar S. Sorzano, Javier Vargas
Loss of high-frequency contrast in cryo-EM maps can complicate atomic model interpretation, while global B-factor correction struggles to account for differences in quality across regions. DeepEMhancer uses deep learning to automate map post-processing, combining operations resembling masking and sharpening in a single step. Training pairs consist of experimental maps and maps sharpened with the aid of their corresponding atomic models, allowing the network to learn how to improve local features and noise characteristics. Evaluation on 20 experimental maps showed reduced noise and more discernible detail, with an RNA polymerase structure illustrating the method's application. The method improves map interpretability; a clearer post-processed map should not be treated as new, independent experimental evidence. Structural conclusions must still be grounded in the original data and model–map agreement.
Highlight · DeepEMhancer combines masking- and sharpening-like processing to improve local interpretability in cryo-EM maps.
04 · CryoMV: Structure-Prior-Guided Modeling and Real-Particle Validation of Continuous Conformational Transitions in Cryo-EM
Preprint · Publication/issue date: 2026-09-27
Authors: Fuwei Li, Hao Dong, Shuai Tang, Xinsheng Wang, Chuanyang Zhang, Chenxuan Ji, Renmin Han, Fa Zhang, Xiaohua Wan
When recovering continuous conformational changes from 2D particle images, a model can generate smooth trajectories without every intermediate state necessarily being supported by real data. This preprint introduces CryoMV, which combines modeling guided by structural priors with validation against original particle images. The framework first uses a reference density to establish structural anchors and motion priors, then maps candidate paths onto 2D particle data, evaluating candidate conformations with particle poses and contrast transfer functions taken into account. Supported states are reconstructed by back-projecting the original particles and assessed using half-maps and FSC. The authors report performance on two EMPIAR datasets in terms of robustness, verifiability, and reconstruction resolution. The aim is to provide traceable particle evidence for generated conformations and reduce model-induced artifacts in continuous heterogeneity analysis, rather than treating a smooth transition as validation in itself.
Highlight · CryoMV connects candidate conformational paths to reconstructions from real particles to test whether intermediate states have experimental support.
05 · A reversible allosteric inhibitor of GlyT2 alleviates neuropathic pain without on-target side effects
Preprint · Publication/issue date: 2025-11-20
Authors: Ryan P. Cantwell Chater, Julian Peiser-Oliver, Tanmay K. Pati, Ada S. Quinn, Irina Lotsaris, Zachary J. Frangos, Kristen E. Anderson, Anna E. Tischer, Billy J. Williams-Noonan, Karin R. Aubrey, Megan L. O’Mara, Michael Michaelides, Sarasa A. Mohammadi, Christopher L. Cioffi, Robert J. Vandenberg, Azadeh Shahsavar
GlyT2 regulates inhibitory glycinergic neurotransmission and is an important target in non-opioid analgesic research. However, some inhibitors cause side effects because their inhibition is difficult to reverse at analgesic doses. This preprint develops the reversible allosteric inhibitor RPI-GLYT2-82 and uses cryo-EM structures of human GlyT2 to locate its binding region and compare conformations in the substrate-free, glycine-bound, and inhibitor-bound states. The authors report that the compound dissociates faster than the quasi-irreversible inhibitor ORG25543 and relieves pain in a mouse model of neuropathic pain, with no observed signs of the on-target side effects or addiction risk assessed. The work suggests that reversibility may influence the balance between efficacy and safety. These findings are animal evidence reported in a preprint, however, and cannot be directly extrapolated to safety in humans.
Highlight · Reversible allosteric inhibition offers a way to balance inhibitory potency with recovery of function in GlyT2 analgesic research.
06 · Structural considerations on xeGlyT2 substrate and inhibitor recognition
Proceedings of the National Academy of Sciences · Publication/issue date: 2026-10-13
Authors: Ryan P. Cantwell Chater, Azadeh Shahsavar
No abstract was saved in Zotero. Checks of the original DOI landing page and publisher metadata also yielded no usable abstract, so this issue lists metadata only.
07 · Mechanisms of transport and analgesic compounds recognition by glycine transporter 2
Proceedings of the National Academy of Sciences · Publication/issue date: 2025-12-02
Authors: Yuhang Wang, Jiawei Su, Jun Zhao, Renjie Li, Qinru Bai, Hongyi Song, Yufei Meng, Qiao Ma, Yan Zhao
GlyT2 maintains inhibitory neurotransmission by recycling glycine, with substrate transport and drug inhibition involving multiple conformational states. This study obtained high-resolution structures without ligand and with glycine or several candidate analgesic inhibitors bound, spanning outward-open, occluded, and inward-open states. Substrate complexes reveal how glycine, sodium, and chloride bind and suggest a third sodium-binding site, offering an explanation for ion-coupled transport. The authors also identified an allosteric pocket for the lipid-based inhibitor oleoyl-D-lysine and propose that it prevents conformational transitions by stabilizing an outward-facing state. Other small-molecule complexes reveal distinct modes of competitive or allosteric inhibition. The work provides a structural framework for comparing glycine reuptake with the actions of candidate drugs, but the structures alone do not establish the compounds' clinical analgesic efficacy.
Highlight · GlyT2 structures in multiple conformations link ion-coupled transport to the mechanisms of different inhibitors.
Authors: Wenming Ji, Yuanzhi Yu, Zirui Liu, Junwen Su, Qianyu Wang, Mulin Lai, Jing-Xiang Wu
Human GlyT2 uses sodium and chloride gradients to take glycine back up into presynaptic neurons, making it essential for maintaining inhibitory signaling. This study resolved multiple ligand-free, substrate-bound, and inhibitor-bound structures: the ligand-free state faces inward, while glycine binds in the central pocket of an occluded conformation. ORG25543 and opiranserin occupy allosteric sites near the extracellular pathway, where the authors propose that they act as wedges, hindering the movement of relevant transmembrane helices and closure of the extracellular gate. Comparisons across states also reveal local and global changes accompanying ion and glycine binding and release. These observations provide human structural evidence for mechanistic studies of a non-opioid analgesic target and facilitate comparisons with other GlyT2 studies that differ in species, conformational states, and ligands.
Highlight · Structural snapshots of human GlyT2 explain how substrate transport and allosteric inhibition act on the same conformational cycle.
Authors: Chuancun Wei, Katherine A. Abrahams, Violetta Krisilia, Jian Li, Sudagar S. Gurcha, Eveline Derr, Milena Hänisch, Rainer Kalscheuer, Gurdyal S. Besra, Zihe Rao, Lu Zhang
Lipid-linked galactan is an important component of the Mycobacterium tuberculosis cell wall, and its transport across the membrane depends on a polysaccharide ABC transport system. This study combines cryo-EM observations of multiple transporter states with cellular functional analyses to examine how substrate recognition connects to energy-driven transport. Some density is consistent with the native substrate, supporting coordination between substrate binding and transporter conformational changes, though the substrate assignment remains suggestive rather than definitive. Together, the structural snapshots provide a framework for understanding cell wall precursor transport and support efforts to identify anti-tuberculosis drug targets in cell wall pathways. The main contribution is insight into fundamental mechanisms: the abstract reports no efficacy of a new drug in humans, and structural observations alone cannot establish clinical utility.
Highlight · Structures in multiple states and functional evidence help explain how M. tuberculosis cell wall components are transported across the membrane.
10 · Enhancement of hippocampal synaptic AMPA receptor function by the antidepressant tianeptine and by opioid peptides
Proceedings of the National Academy of Sciences · Publication/issue date: 2026-10-13
Authors: Anna Mariano, Andrei Rozov, Grant D. Phillips, Sam Singleton, Daniel Baptista-Hon, Fliza Valiullina-Rakhmatullina, Rolf Sprengel, Rosamund Langston, Stephen J. Martin, Tim G. Hales, Jeremy J. Lambert
How the atypical antidepressant tianeptine enhances glutamatergic signaling is a longstanding question tied to its distinctive actions compared with conventional monoaminergic drugs. Using voltage-clamp recordings in mouse hippocampal CA1 pyramidal neurons, this study found that tianeptine enhances evoked excitatory currents mediated by synaptic AMPA receptors, an effect dependent on intracellular polyamines and the GluA1 subunit. The results suggest that the drug may relieve endogenous polyamine block of GluA1-containing channels. Further experiments involving receptor deletion, antagonism, and signaling inhibition support an indirect dependence on μ and δ opioid receptors; corresponding peptide and non-peptide agonists also mimic the effect. The work links opioid receptor activity to the regulation of synaptic excitability, but mechanistic evidence from cells and animals does not directly demonstrate antidepressant efficacy in humans.
Highlight · Tianeptine can indirectly enhance GluA1-containing synaptic AMPA receptor function through opioid receptor signaling.
11 · Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling
Science · Publication/issue date: 2026-10-01
Authors: Iuliia Karavaeva, Astrid Linde Basse, Samuel A. J. Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F. Havelund, Marie Sophie Isidor, Adam Chatoff, Andrea Andress Huacachino, Hannah J. Richter, Meghna Birla, Sabina Chubanava, Yann Deleye, Rini Arianti, David Tandio, Sarah E. Utzon, Zafir Kaiser, Yachen Shen, Ditte Neess, Hannes Embring, Dilip Menon, Olivia J. Conway, Frederike Sass, Fabian Finger, Lidia Argemi-Muntadas, Tao Ma, Elahu G. Sustarsic, Cecilie Kynding Kristensen, Rebecca L. McIntyre, Genesee J. Martinez, Anna Sofie Husted, Matthew J. Emmett, Zachary A. Kipp, Mikkel Frost, Mark P. Jedrychowski, Michel Van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W. McGarrah, Kaja Plucińska, Mohit K. Midha, Andreas Prokesch, Paul Cohen, James G. Granneman, Patrick Seale, Riekelt H. Houtkooper, Jacob B. Hansen, Steven P. Gygi, Thue W. Schwartz, Matthew P. Gillum, Terry D. Hinds, Raymond E. Soccio, Phillip J. White, Edmund R. S. Kunji, Thomas Moritz, Jonas T. Treebak, Endre Kristóf, Susanne Mandrup, Brice Emanuelli, Nathaniel W. Snyder, Daniel J. Fazakerley, Lawrence Kazak, Nils J. Færgeman, Mitchell A. Lazar, Zachary Gerhart-Hines
Adipocytes respond to circadian rhythms while also needing to adjust energy metabolism rapidly as diet and temperature change. This study identifies the mitochondrial carrier SLC25A34 as a point of convergence for these signals. During the sleep phase, REV-ERB transcriptional repressors suppress its expression; the active phase, a high-fat diet, or cold exposure can lift this repression and promote expression through lipolytic signaling and PPAR. Biochemical and metabolic findings support a functional model in which SLC25A34 imports oxaloacetate into mitochondria, supporting both the tricarboxylic acid cycle and the production of cytosolic acetyl-CoA. The latter supports lipid synthesis and expression of genes associated with mitochondrial oxidation, coordinating lipid breakdown and resynthesis. This mechanism helps explain how thermogenic fat combines daily rhythms with acute responses, though the proposed transport substrate and potential therapeutic implications should still be interpreted in light of the strength of the respective evidence.
Highlight · SLC25A34 connects circadian clock, dietary, and temperature signals to lipid cycling in adipocytes.
12 · The cellular landscape of druggable RNA-binding proteins
Nature Reviews Drug Discovery · Publication/issue date: 2026-09-29
Authors: Gaia Di Timoteo, Benson M. George, Omar Abdel-Wahab, Ryan A. Flynn, Konstantinos Tzelepis
RNA-binding proteins participate in RNA processing, modification, translation, and degradation and also influence non-coding RNA function, linking them closely to cell identity and many diseases. This review summarizes their established intracellular roles, focuses on their connections to cancer, and discusses how systematic studies of the RNA interactome have broadened the range of potential drug targets. It also explores an emerging direction: some RNA-binding proteins occur on the cell surface, with distributions associated with cell type or disease state. These surface proteins could serve as biomarkers or immunotherapy targets, and the authors discuss strategies for exploiting their localization to develop new immunotherapies. The field is still developing, however, and cell-surface localization alone does not establish a protein as a reliable, specific target for clinical use.
Highlight · Cell-surface localization of RNA-binding proteins broadens the scope of research into biomarkers and immunotherapy targets.
This issue features 12 papers covering cryo-EM sample preparation and data processing, GlyT2 transport and analgesia, synaptic signaling, lipid metabolism, and RNA-binding proteins as drug targets.
Cryo-EM Sample Preparation and Data Processing (4 papers)
01 · Post-acquisition super resolution for cryo-electron microscopy
IUCrJ · Publication/issue date: 2026-09-01
Authors: R. N. Burton Smith, K. Murata
When a cryo-EM reconstruction approaches the Nyquist limit imposed by pixel sampling, further improvements in resolution usually require changes to acquisition conditions. This study introduces post-acquisition super resolution (PASR), which doubles the pixel sampling of raw counting-mode movies before motion correction, potentially allowing reconstructions from existing data to exceed the physical sampling limit. The authors tested the approach on samples of various sizes and symmetries and report that it can also be applied to data acquired in super-resolution mode. The method may reduce the magnification needed to reach a target resolution, improving acquisition efficiency. A key prerequisite, however, is that the raw data already reach the relevant Nyquist limit: doubling the pixel sampling does not create genuine structural information out of nothing in an arbitrary dataset.
Highlight · PASR offers a post-processing route to extract more structural information from movie data that have already reached their sampling limit.
DOI: 10.1107/S2052252526005348
02 · Plunge freezing tweezers with ultrasonic excitation for reducing preferred particle orientation in cryo-EM
Preprint · Publication/issue date: 2026-10-04
Authors: Jakub Wenz, Mischa Flór, Constantin R. Krüger, Marcel Drabbels, Ulrich J. Lorenz
Particle adsorption at the air–water interface can cause preferred orientation, leaving some views heavily overrepresented and others entirely absent. This preprint integrates an ultrasonic transducer into the sample-holding plunge-freezing tweezers to excite the sample during vitrification and improve its angular distribution. The authors previously proposed detaching particles from the air–water interface so that their orientations could redistribute; this work focuses on an implementation compatible with plunge-freezing equipment. In tests with hemagglutinin, which is prone to preferred orientation, the proportion of side and tilted views increased with excitation amplitude, ultimately yielding a complete trimer reconstruction at 2.5 Å. The results show that active perturbation during sample preparation can improve orientation coverage, but the demonstrated benefits come from a specific test system and require evaluation in other samples.
Highlight · Integrating ultrasonic excitation into plunge-freezing tweezers can improve particle view coverage during sample preparation.
DOI: 10.64898/2026.09.29.755300
03 · DeepEMhancer: a deep learning solution for cryo-EM volume post-processing
Communications Biology · Publication/issue date: 2021-07-15
Authors: Ruben Sanchez-Garcia, Josue Gomez-Blanco, Ana Cuervo, Jose Maria Carazo, Carlos Oscar S. Sorzano, Javier Vargas
Loss of high-frequency contrast in cryo-EM maps can complicate atomic model interpretation, while global B-factor correction struggles to account for differences in quality across regions. DeepEMhancer uses deep learning to automate map post-processing, combining operations resembling masking and sharpening in a single step. Training pairs consist of experimental maps and maps sharpened with the aid of their corresponding atomic models, allowing the network to learn how to improve local features and noise characteristics. Evaluation on 20 experimental maps showed reduced noise and more discernible detail, with an RNA polymerase structure illustrating the method's application. The method improves map interpretability; a clearer post-processed map should not be treated as new, independent experimental evidence. Structural conclusions must still be grounded in the original data and model–map agreement.
Highlight · DeepEMhancer combines masking- and sharpening-like processing to improve local interpretability in cryo-EM maps.
DOI: 10.1038/s42003-021-02399-1
04 · CryoMV: Structure-Prior-Guided Modeling and Real-Particle Validation of Continuous Conformational Transitions in Cryo-EM
Preprint · Publication/issue date: 2026-09-27
Authors: Fuwei Li, Hao Dong, Shuai Tang, Xinsheng Wang, Chuanyang Zhang, Chenxuan Ji, Renmin Han, Fa Zhang, Xiaohua Wan
When recovering continuous conformational changes from 2D particle images, a model can generate smooth trajectories without every intermediate state necessarily being supported by real data. This preprint introduces CryoMV, which combines modeling guided by structural priors with validation against original particle images. The framework first uses a reference density to establish structural anchors and motion priors, then maps candidate paths onto 2D particle data, evaluating candidate conformations with particle poses and contrast transfer functions taken into account. Supported states are reconstructed by back-projecting the original particles and assessed using half-maps and FSC. The authors report performance on two EMPIAR datasets in terms of robustness, verifiability, and reconstruction resolution. The aim is to provide traceable particle evidence for generated conformations and reduce model-induced artifacts in continuous heterogeneity analysis, rather than treating a smooth transition as validation in itself.
Highlight · CryoMV connects candidate conformational paths to reconstructions from real particles to test whether intermediate states have experimental support.
DOI: 10.64898/2026.09.21.753206
GlyT2 Transport and Analgesia (4 papers)
05 · A reversible allosteric inhibitor of GlyT2 alleviates neuropathic pain without on-target side effects
Preprint · Publication/issue date: 2025-11-20
Authors: Ryan P. Cantwell Chater, Julian Peiser-Oliver, Tanmay K. Pati, Ada S. Quinn, Irina Lotsaris, Zachary J. Frangos, Kristen E. Anderson, Anna E. Tischer, Billy J. Williams-Noonan, Karin R. Aubrey, Megan L. O’Mara, Michael Michaelides, Sarasa A. Mohammadi, Christopher L. Cioffi, Robert J. Vandenberg, Azadeh Shahsavar
GlyT2 regulates inhibitory glycinergic neurotransmission and is an important target in non-opioid analgesic research. However, some inhibitors cause side effects because their inhibition is difficult to reverse at analgesic doses. This preprint develops the reversible allosteric inhibitor RPI-GLYT2-82 and uses cryo-EM structures of human GlyT2 to locate its binding region and compare conformations in the substrate-free, glycine-bound, and inhibitor-bound states. The authors report that the compound dissociates faster than the quasi-irreversible inhibitor ORG25543 and relieves pain in a mouse model of neuropathic pain, with no observed signs of the on-target side effects or addiction risk assessed. The work suggests that reversibility may influence the balance between efficacy and safety. These findings are animal evidence reported in a preprint, however, and cannot be directly extrapolated to safety in humans.
Highlight · Reversible allosteric inhibition offers a way to balance inhibitory potency with recovery of function in GlyT2 analgesic research.
DOI: 10.1101/2025.04.21.649698
06 · Structural considerations on xeGlyT2 substrate and inhibitor recognition
Proceedings of the National Academy of Sciences · Publication/issue date: 2026-10-13
Authors: Ryan P. Cantwell Chater, Azadeh Shahsavar
No abstract was saved in Zotero. Checks of the original DOI landing page and publisher metadata also yielded no usable abstract, so this issue lists metadata only.
DOI: 10.1073/pnas.2612775123
07 · Mechanisms of transport and analgesic compounds recognition by glycine transporter 2
Proceedings of the National Academy of Sciences · Publication/issue date: 2025-12-02
Authors: Yuhang Wang, Jiawei Su, Jun Zhao, Renjie Li, Qinru Bai, Hongyi Song, Yufei Meng, Qiao Ma, Yan Zhao
GlyT2 maintains inhibitory neurotransmission by recycling glycine, with substrate transport and drug inhibition involving multiple conformational states. This study obtained high-resolution structures without ligand and with glycine or several candidate analgesic inhibitors bound, spanning outward-open, occluded, and inward-open states. Substrate complexes reveal how glycine, sodium, and chloride bind and suggest a third sodium-binding site, offering an explanation for ion-coupled transport. The authors also identified an allosteric pocket for the lipid-based inhibitor oleoyl-D-lysine and propose that it prevents conformational transitions by stabilizing an outward-facing state. Other small-molecule complexes reveal distinct modes of competitive or allosteric inhibition. The work provides a structural framework for comparing glycine reuptake with the actions of candidate drugs, but the structures alone do not establish the compounds' clinical analgesic efficacy.
Highlight · GlyT2 structures in multiple conformations link ion-coupled transport to the mechanisms of different inhibitors.
DOI: 10.1073/pnas.2506722122
08 · Transport and inhibition mechanisms of human glycine transporter 2
Nature Communications · Publication/issue date: 2026-04-16
Authors: Wenming Ji, Yuanzhi Yu, Zirui Liu, Junwen Su, Qianyu Wang, Mulin Lai, Jing-Xiang Wu
Human GlyT2 uses sodium and chloride gradients to take glycine back up into presynaptic neurons, making it essential for maintaining inhibitory signaling. This study resolved multiple ligand-free, substrate-bound, and inhibitor-bound structures: the ligand-free state faces inward, while glycine binds in the central pocket of an occluded conformation. ORG25543 and opiranserin occupy allosteric sites near the extracellular pathway, where the authors propose that they act as wedges, hindering the movement of relevant transmembrane helices and closure of the extracellular gate. Comparisons across states also reveal local and global changes accompanying ion and glycine binding and release. These observations provide human structural evidence for mechanistic studies of a non-opioid analgesic target and facilitate comparisons with other GlyT2 studies that differ in species, conformational states, and ligands.
Highlight · Structural snapshots of human GlyT2 explain how substrate transport and allosteric inhibition act on the same conformational cycle.
DOI: 10.1038/s41467-026-71935-6
Other Papers (4 papers)
09 · Recognition and mechanism of M. tuberculosis cell wall galactan transport
Nature Communications · Publication/issue date: 2026-10-09
Authors: Chuancun Wei, Katherine A. Abrahams, Violetta Krisilia, Jian Li, Sudagar S. Gurcha, Eveline Derr, Milena Hänisch, Rainer Kalscheuer, Gurdyal S. Besra, Zihe Rao, Lu Zhang
Lipid-linked galactan is an important component of the Mycobacterium tuberculosis cell wall, and its transport across the membrane depends on a polysaccharide ABC transport system. This study combines cryo-EM observations of multiple transporter states with cellular functional analyses to examine how substrate recognition connects to energy-driven transport. Some density is consistent with the native substrate, supporting coordination between substrate binding and transporter conformational changes, though the substrate assignment remains suggestive rather than definitive. Together, the structural snapshots provide a framework for understanding cell wall precursor transport and support efforts to identify anti-tuberculosis drug targets in cell wall pathways. The main contribution is insight into fundamental mechanisms: the abstract reports no efficacy of a new drug in humans, and structural observations alone cannot establish clinical utility.
Highlight · Structures in multiple states and functional evidence help explain how M. tuberculosis cell wall components are transported across the membrane.
DOI: 10.1038/s41467-026-78496-8
10 · Enhancement of hippocampal synaptic AMPA receptor function by the antidepressant tianeptine and by opioid peptides
Proceedings of the National Academy of Sciences · Publication/issue date: 2026-10-13
Authors: Anna Mariano, Andrei Rozov, Grant D. Phillips, Sam Singleton, Daniel Baptista-Hon, Fliza Valiullina-Rakhmatullina, Rolf Sprengel, Rosamund Langston, Stephen J. Martin, Tim G. Hales, Jeremy J. Lambert
How the atypical antidepressant tianeptine enhances glutamatergic signaling is a longstanding question tied to its distinctive actions compared with conventional monoaminergic drugs. Using voltage-clamp recordings in mouse hippocampal CA1 pyramidal neurons, this study found that tianeptine enhances evoked excitatory currents mediated by synaptic AMPA receptors, an effect dependent on intracellular polyamines and the GluA1 subunit. The results suggest that the drug may relieve endogenous polyamine block of GluA1-containing channels. Further experiments involving receptor deletion, antagonism, and signaling inhibition support an indirect dependence on μ and δ opioid receptors; corresponding peptide and non-peptide agonists also mimic the effect. The work links opioid receptor activity to the regulation of synaptic excitability, but mechanistic evidence from cells and animals does not directly demonstrate antidepressant efficacy in humans.
Highlight · Tianeptine can indirectly enhance GluA1-containing synaptic AMPA receptor function through opioid receptor signaling.
DOI: 10.1073/pnas.2521987123
11 · Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling
Science · Publication/issue date: 2026-10-01
Authors: Iuliia Karavaeva, Astrid Linde Basse, Samuel A. J. Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F. Havelund, Marie Sophie Isidor, Adam Chatoff, Andrea Andress Huacachino, Hannah J. Richter, Meghna Birla, Sabina Chubanava, Yann Deleye, Rini Arianti, David Tandio, Sarah E. Utzon, Zafir Kaiser, Yachen Shen, Ditte Neess, Hannes Embring, Dilip Menon, Olivia J. Conway, Frederike Sass, Fabian Finger, Lidia Argemi-Muntadas, Tao Ma, Elahu G. Sustarsic, Cecilie Kynding Kristensen, Rebecca L. McIntyre, Genesee J. Martinez, Anna Sofie Husted, Matthew J. Emmett, Zachary A. Kipp, Mikkel Frost, Mark P. Jedrychowski, Michel Van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W. McGarrah, Kaja Plucińska, Mohit K. Midha, Andreas Prokesch, Paul Cohen, James G. Granneman, Patrick Seale, Riekelt H. Houtkooper, Jacob B. Hansen, Steven P. Gygi, Thue W. Schwartz, Matthew P. Gillum, Terry D. Hinds, Raymond E. Soccio, Phillip J. White, Edmund R. S. Kunji, Thomas Moritz, Jonas T. Treebak, Endre Kristóf, Susanne Mandrup, Brice Emanuelli, Nathaniel W. Snyder, Daniel J. Fazakerley, Lawrence Kazak, Nils J. Færgeman, Mitchell A. Lazar, Zachary Gerhart-Hines
Adipocytes respond to circadian rhythms while also needing to adjust energy metabolism rapidly as diet and temperature change. This study identifies the mitochondrial carrier SLC25A34 as a point of convergence for these signals. During the sleep phase, REV-ERB transcriptional repressors suppress its expression; the active phase, a high-fat diet, or cold exposure can lift this repression and promote expression through lipolytic signaling and PPAR. Biochemical and metabolic findings support a functional model in which SLC25A34 imports oxaloacetate into mitochondria, supporting both the tricarboxylic acid cycle and the production of cytosolic acetyl-CoA. The latter supports lipid synthesis and expression of genes associated with mitochondrial oxidation, coordinating lipid breakdown and resynthesis. This mechanism helps explain how thermogenic fat combines daily rhythms with acute responses, though the proposed transport substrate and potential therapeutic implications should still be interpreted in light of the strength of the respective evidence.
Highlight · SLC25A34 connects circadian clock, dietary, and temperature signals to lipid cycling in adipocytes.
DOI: 10.1126/science.adz4797
12 · The cellular landscape of druggable RNA-binding proteins
Nature Reviews Drug Discovery · Publication/issue date: 2026-09-29
Authors: Gaia Di Timoteo, Benson M. George, Omar Abdel-Wahab, Ryan A. Flynn, Konstantinos Tzelepis
RNA-binding proteins participate in RNA processing, modification, translation, and degradation and also influence non-coding RNA function, linking them closely to cell identity and many diseases. This review summarizes their established intracellular roles, focuses on their connections to cancer, and discusses how systematic studies of the RNA interactome have broadened the range of potential drug targets. It also explores an emerging direction: some RNA-binding proteins occur on the cell surface, with distributions associated with cell type or disease state. These surface proteins could serve as biomarkers or immunotherapy targets, and the authors discuss strategies for exploiting their localization to develop new immunotherapies. The field is still developing, however, and cell-surface localization alone does not establish a protein as a reliable, specific target for clinical use.
Highlight · Cell-surface localization of RNA-binding proteins broadens the scope of research into biomarkers and immunotherapy targets.
DOI: 10.1038/s41573-026-01531-2