Biophysics

Structural insights into the orthosteric inhibition of P2X receptors by non-ATP analog antagonists

1. Danqi Sheng
2. Chen-Xi Yue
3. Fei Jin
4. Yao Wang
5. Muneyoshi Ichikawa
6. Ye Yu
7. Chang-Run Guo
8. Motoyuki Hattori

• Curated by eLife

  eLife assessment

  This study by Sheng and colleagues provides valuable insights into the mechanism of competitive inhibitors of P2X receptors. The structural and functional evidence supporting the subtype specificity of pyridoxal-5'-phosphate derivatives is compelling and provides information for designing drugs that selectively target different subtypes of P2X receptor channels. The work will be of interest to biochemists, structural biologists, and pharmacologists.

Reviewed by eLife

Microtubules under mechanical pressure can breach dense actin networks

1. Matthieu Gélin
2. Alexandre Schaeffer
3. Jérémie Gaillard
4. Christophe Guérin
5. Benoit Vianay
6. Magali Orhant-Prioux
7. Marcus Braun
8. Christophe Leterrier
9. Laurent Blanchoin
10. Manuel Théry

Reviewed by Review Commons

Diffusive mediator feedback explains the health-to-disease transition of skin inflammation

1. Maki Sudo
2. Koichi Fujimoto

Reviewed by Review Commons

Conformational dynamics of a nicotinic receptor neurotransmitter site

1. Mrityunjay Singh
2. Dinesh C. Indurthi
3. Lovika Mittal
4. Anthony Auerbach
5. Shailendra Asthana

• Curated by eLife

  eLife assessment

  This useful work provides insight into agonist binding to nicotinic acetylcholine receptors, which is the stimulus for channel activation that regulates muscle contraction at the neuromuscular junction. The authors use in silico methods to explore the transient conformational change from a low to high affinity agonist-bound conformation as occurs during channel opening, but for which structural information is lacking owing to its transient nature. The evidence supporting the main conclusion that ligands flip ~180 degrees in the binding site as it transitions from a low to high affinity bound conformation is incomplete because little support is available for the starting low affinity docked conformations, and the rather approximate methods for computing binding free energies differ significantly from experimental measures for two of the four tested ligands. Nonetheless, this work presents an intriguing possibility for the nature of a transient conformational change at the agonist binding site correlated with channel opening. If the ligand flip observed in these simulations can be reproduced or verified by other studies, then this work would stand as a significant advance in our knowledge of nicotinic receptor gating.

Reviewed by eLife

Constitutive activity of ionotropic glutamate receptors via a hydrophobic plug in the ligand-binding domain

1. Sandra Seljeset
2. Oksana Sintsova
3. Yuhong Wang
4. Hassan Y. Harb
5. Timothy Lynagh

• Curated by Biophysics Colab

  Evaluation statement (8 March 2024)

  Seljeset et al. investigate the mechanism by which NMDA receptors are activated by co-agonists glutamate and glycine. By mutating residue Asp732 in the glycine-binding site, they generate receptors activated by glutamate, and not glycine, but inhibited by glycine antagonists. Conventional and unnatural amino acid mutagenesis reveals that Asp732 interacts with nearby residues to influence channel gating as well as ligand binding. Furthermore, a homomeric receptor from Trichoplax adhaerens, which has a tyrosine in the homologous position, displays constitutive activity that becomes glycine-dependent when the tyrosine is mutated to aspartate. The study is valuable because it reveals the importance of position 732 for controlling ligand potency and channel activity in glutamate receptors, which should lead to a better understanding of how these receptors are primed for channel opening.

  Biophysics Colab recommends this study to scientists interested in the structure and function of glutamate receptors

  Biophysics Colab has evaluated this study as one that meets the following criteria:

  • Rigorous methodology
  • Transparent reporting
  • Appropriate interpretation

  (This evaluation refers to version 2 of this preprint, which has been revised in response to peer review of version 1.)

Reviewed by Biophysics Colab

A novel bivalent interaction mode underlies a non-catalytic mechanism for Pin1-mediated Protein Kinase C regulation

1. Xiao-Ru Chen
2. Karuna Dixit
3. Yuan Yang
4. Mark I. McDermott
5. Hasan T. Imam
6. Vytas A. Bankaitis
7. Tatyana I. Igumenova

• Curated by eLife

  eLife assessment

  Pin1 as an essential prolyl cis/trans isomerase has attracted considerable attention because this enzyme family is implicated in cancer and neurodegenerative diseases. However, the requirement for its catalytic function remains a matter of dispute. The authors provide solid evidence that Pin1 modulates the activity of an important cell signaling kinase, Protein Kinase C, by a non-catalytic mechanism, acting as a chaperone to regulate the stability of this kinase.

Reviewed by eLife

Optical mapping of ground reaction force dynamics in freely behaving Drosophila melanogaster larvae

1. Jonathan H Booth
2. Andrew T Meek
3. Nils M Kronenberg
4. Stefan R Pulver
5. Malte C Gather

• Curated by eLife

  eLife assessment

  This study reports important findings about new locomotory dynamics of crawling Drosophila larva based on imaging the reaction forces during larval crawling. The evidence with the new high-resolution microscopy method is compelling, as it significantly improves the spatial, temporal, and force resolution compared to previous methods for studying Drosophila larva and could be applied to other crawling organisms. The manuscript explains the new technology, WARP microscopy, and provides analysis of the data to characterize small animal behavior and discover new crawling-associated anatomical features and motor patterns. The work will be of interest to the broad neuroscience community interested in the mechanisms of locomotion in a highly tractable model.

Reviewed by eLife

Cryo-EM structure of Slo1 with the auxiliary γ1 subunit suggests mechanism of depolarization-independent activation

1. Milena Redhardt
2. Stefan Raunser
3. Tobias Raisch

Reviewed by Review Commons

Dynamic 1D search and processive nucleosome translocations by RSC and ISW2 chromatin remodelers

1. Jee Min Kim
2. Claudia C Carcamo
3. Sina Jazani
4. Zepei Xie
5. Xinyu A Feng
6. Maryam Yamadi
7. Matthew Poyton
8. Katie L Holland
9. Jonathan B Grimm
10. Luke D Lavis
11. Taekjip Ha
12. Carl Wu

• Curated by eLife

  eLife assessment

  This manuscript describes fundamental single-molecule correlative force and fluorescence microscopy experiments to visualize the 1D diffusion dynamics and long-range nucleosome sliding activity of the yeast chromatin remodelers, RSC and ISW2. Compelling evidence shows that both remodelers exhibit 1D diffusion on bare DNA but utilize different mechanisms, with RSC primarily hopping and ISW2 mainly sliding on DNA. These results will be of interest to researchers working on chromatin remodeling.

Reviewed by eLife

A binding site for phosphoinositides described by multiscale simulations explains their modulation of voltage-gated sodium channels

1. Yiechang Lin
2. Elaine Tao
3. James P Champion
4. Ben Corry

• Curated by eLife

  eLife assessment

  This important study employs multiscale simulations to show that PIP2 lipids bind to DIV S4-S5 linkers within the inactivated state of a voltage-gated sodium channel, affecting the coupling of voltage sensors to the ion-conducting pore. The authors demonstrate that PIP2 prolongs inactivation by binding to the same site that binds the C-terminal during recovery from inactivation, and they suggest that binding to gating charges in the resting state may impede activation, both findings that contribute to our understanding of sodium channel modulation. The coarse-grained and atomistic molecular dynamics simulations are convincing, including state dependence and linker mutants to back up the claims.

Reviewed by eLife