Structural Biology and Molecular Biophysics

eLife assessment

Hyperpolarised-activated and Cyclic Nucleotide-gated (HCN) channels are the only mammalian channels to open under hyperpolarisation, being important for their roles in cardiac and neuronal cells. The authors of this study use atomistic simulations to enforce changing interaction distances that have been identified from a cryoEM structure and a homology model based on the hERG channel. The simulations suggest state-dependent interactions involving pore and voltage sensor helices, as well as with lipids, leading the authors to propose a domino-like mechanism of activation. These findings will be of considerable interest to the ion channel community.

eLife assessment

This valuable study investigates the environmental drivers behind termite construction, focusing, in particular, on pellet deposition behavior, with the conclusion that termites likely sense curvature indirectly through substrate evaporation. The findings reconcile discrepancies between previous studies through experimental and computational approaches. The strength of the evidence supporting the claims is solid, although many computational details are still missing, and the are concerns about the repeatability of the results across replicates, the dynamics of evaporation in their experiment, and the termites' ability to sense humidity.

eLife assessment

This potentially important work proposes a novel approach, based on co-evolution analysis, machine-learning protocols and molecular dynamics simulations, to predict structures and energetics of the main states of the alternating access cycle of a family of membrane transporters, the sugar porters. The approach is compelling, especially the application of co-evolution and Alphafold to generate highly accurate models in different conformational states of a given protein, but the work is currently incomplete due to shortcomings in the calculation of the energy landscape. With this aspect strengthened, the manuscript will be of interest to the transporter and computational modeling communities.

eLife assessment

This study reports a joint experimental and computational investigation of the structural features of biomolecular condensates formed by a specific intrinsically disordered protein. The authors also adapt emerging rules to discuss and physico-chemical determinants of these structures of condensates. Specifically, the authors adapt the analysis of fractal structures, co-opted from the field of colloidal chemistry / physics, and generate important insights regarding the network-like organization of disordered proteins within in silico facsimiles of condensates. The usage of these analyses in the context of studying all atom models for multi-chain assemblies intended to mimic the internal organization of condensates is very interesting. The work is of relevance to cell biology and structural biology.

eLife assessment

This work presents an important methodological advance for single-molecule force spectroscopy of membrane proteins providing a new robust design of the linkage between a target single molecule and solid support. The data provide compelling evidence of the improved mechanical stability of the pulling system. Allowing more statistically reliable force measurements of biomolecules, this method may be broadly applicable in the field of single-molecule biophysics.

eLife assessment

This paper presents important findings on the hexametric structure of MCM8/9, which potentially explain its role as a DNA helicase in homologous recombination. This solid work will be of interest to biologists studying DNA transactions.

eLife assessment

This is an important report on the discovery of a strong sensitizing effect of cannabidiol on the activation of TRPV2 channels by 2-APB. The conclusions are convincingly supported by solid electrophysiological recordings and cryo-EM structures, but identification of a clear molecular mechanism will require additional structural work. The paper will be of interest to the ion channel research community.

eLife assessment

This study represents a valuable mechanistic contribution towards understanding how ribosomal RNA is processed during ribosome biogenesis. The biochemical evidence supporting the major conclusions is solid, but the structural biology data is incomplete and would benefit from more rigorous analysis. After further strengthening, this work would be of interest to cell biologists and biochemists working on ribosome biogenesis.

eLife assessment

This is a valuable study, carried out in a solid and comprehensive manner. The results advance the understanding of one of the steps of the HIV life cycle, via a better description of the mechanisms underlying Gag-Pol dimerization.

eLife assessment

The authors use a combination of structural and MD simulation approaches to characterize phospholipid interactions with the pentameric ligand-gated ion channel, GLIC. The general agreement between structures and simulations increases confidence in the description of the lipid interaction poses, and provides a solid basis for the prediction of a state dependent interaction site where lipids could dynamically modulate channel gating. The results will be very useful to understand the nature of phospholipid interactions with pentameric ligand-gated ion channels, although the functional or structural significance of these lipid interactions remains unclear.

eLife assessment

This important interdisciplinary study substantially advances our understanding of the prolactin receptor interactions with the membrane lipids and the effect of these interactions on cell signaling. The authors use a combination of state-of-the-art NMR structural analysis, simulations, and cellular assays to provide compelling experimental evidence for protein complexes being regulated by IDR-membrane interactions. The work will be of broad interest to structural biologists and biochemists, and the results presented herein are likely relevant for other non-tyrosine kinase receptors.

eLife assessment

Using surface micropatterning, optical activation, and theoretical analysis, the authors provide compelling evidence that adjacent cells actively propagate mechanical stress in epithelial tissues. The response of the receiver cell is active and enhanced when the principal stress direction is perpendicular to the orientation of actin fibers. This work is important and a must-read for everybody wanting to understand tissue mechanics.

eLife assessment

This fundamental work substantially advances our understanding of polymer physics underpinnings of genome folding, organization, and regulation. The conclusions are supported by both convincing computer simulations and analytical theory. The work will be of significant interest to the genome folding community.

eLife assessment

This important manuscript combines cryo-EM and a suite of compelling whole cell and proteoliposome transport assays to establish the mechanism and structure of the full-length human SLC26A6 chloride/bicarbonate exchangers, including the first partial view of the previously unresolved IVS region of an SLC26 STAS domain. In combination with prior studies on additional SLC26 paralogs, including the SLC26A9 paralog initially reported by the same group, the study provides broadly relevant insights into the mechanistic diversity of the SLC26 transporters. This study is of interest to the biophysics community and the field of membrane transport.

eLife assessment

This important and elegant study uses experimental structural data, ion affinity measurements, and computational methods to provide insight into the thermodynamic landscape of cation transporters of the Cation Diffusion Facilitator (CDF) superfamily, together with a detailed structural investigation of the role of the three zinc(II) binding sites of the YiiP family member. Overall, the support for the proposed transport cycle of YiiP is compelling. This work will be of interest to biologists and biophysics who work with membrane transporters.

eLife assessment

In this valuable study, the authors report a structural model of full-length kinesin-1, describing its autoinhibitory mechanism using cryo-EM, AlphaFold structural predictions, cross-linking, and mass spectrometry, which together indicate that the previous model for kinesin-1 auto-inhibition using a small motif in the kinesin tail was not adequate. The data offer a convincing model for how kinesin-1 is autoinhibited, although the evidence is in some places still incomplete and would thus benefit from additional analyses. The work will be of significant interest to the research community working on cytoplasmic transport and microtubule motors.

eLife assessment

This study provides valuable insight into the diversity within the NRAMP superfamily of transporters. Evidence of divalent metal ion transport and the structure (obtained without added metal ions) are convincing. However, molecular insight into Al3+ recognition and transport is incomplete, and the work would be strengthened by the determination of a metal-bound structure or additional experiments (such as molecular dynamics simulations or quantitative Al3+ binding/transport assays) to support the proposed Al3+ binding site. The work will be of interest to structural biologists and biophysicists studying NRAMP transporters.

eLife assessment

This valuable study discovers that zinc ions can activate some OTOP proton channels, identifying a pharmacological tool for research, and further establishing that OTOP channels gate. The data presented provide convincing support for the conclusions made by the authors, and the study is expected to be of considerable interest to physiologists investigating OTOP and other proton channels.

eLife assessment

The study represents an impressive effort to use atomistic simulations to probe cryptic binding sites in the envelope of six flaviviruses. Moreover, using constant pH simulations, the authors suggest that a cluster of ionizable residues contribute to the pH dependent conformational rearrangements required in the infection process. Therefore, the study provides new mechanistic insights that can be helpful in future efforts to develop drugs that target flaviviruses.

eLife assessment

This theoretical work deals with the problem of homeostasis of protein density within cells, relying on the Pump and Leak model. The model makes predictions both for growing and senescent cells, which they compare to experimental data on budding yeast. The work extends previous works and makes biologically-relevant predictions, which will be of interest to both theorists and experimentalists interested in cell physiology.