Biophysics

PAR recognition by PARP1 regulates DNA‐dependent activities and independently stimulates catalytic activity of PARP1

1. Waghela Deeksha
2. Suman Abhishek
3. Eerappa Rajakumara

Reviewed by Review Commons

Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B

1. Tamar Skaist Mehlman
2. Justin T Biel
3. Syeda Maryam Azeem
4. Elliot R Nelson
5. Sakib Hossain
6. Louise Dunnett
7. Neil G Paterson
8. Alice Douangamath
9. Romain Talon
10. Danny Axford
11. Helen Orins
12. Frank von Delft
13. Daniel A Keedy

• Curated by eLife

  eLife assessment

  Based on two room-temperature X-ray crystallographic screens of PTP1B phosphatase against two sets of chemical fragments, and by comparing the results from a previous cryo screen, the authors report the important observation that, in addition to overlapping but non-identical sets of hits compared to the cryo screen, the room-temperature screens lead to significant differences in terms of binding sites and poses for some of the hits. The study provides compelling support for the use of room-temperature X-ray crystallography in early-stage drug discovery and highlights that temperature should be used as a parameter in efforts to extract additional insight from such analyses.

Reviewed by eLife

Timeline of changes in spike conformational dynamics in emergent SARS-CoV-2 variants reveal progressive stabilization of trimer stalk with altered NTD dynamics

1. Sean M Braet
2. Theresa SC Buckley
3. Varun Venkatakrishnan
4. Kim-Marie A Dam
5. Pamela J Bjorkman
6. Ganesh S Anand

• Curated by eLife

  eLife assessment

  This fundamental and timely study provides insights into the structural dynamics of several relevant mutant forms of SARS-CoV-2 spike protein, including the most recent omicron variant. The hydrogen/deuterium-exchange studies provide compelling evidence for the stabilization of the spike stalk in conjunction with increased dynamics of the N-terminal domain, where binding to the ACE2 receptor occurs. These results have profound implications for the development of small molecule inhibitors of the spike protein-ACE2 receptor interaction.

Reviewed by eLife

DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43

1. Andy Y.W. Lam
2. Kotaro Tsuboyama
3. Hisashi Tadakuma
4. Yukihide Tomari

Reviewed by Review Commons

Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase

1. Zhuoran Zhao
2. Xiayu Shen
3. Shuang Chen
4. Jing Gu
5. Haun Wang
6. Maria F Mojica
7. Moumita Samanta
8. Debsindhu Bhowmik
9. Alejandro J Vila
10. Robert A Bonomo
11. Shozeb Haider

• Curated by eLife

  eLife assessment

  In this useful study, the authors utilize state-of-the-art computational methods complemented with some experimental validation to investigate the dynamics of flexible loops of the L1 Metallo-β-lactamase enzyme, resulting in a better understanding of the various conformational states useful for the rational design of superior β-lactamase inhibitors/antibiotics. The evidence supporting the claims is solid, and the work will be of interest to computational, experimental biologists, and drug designers working on antibiotic resistance.

Reviewed by eLife

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins

1. Alexandria N Miller
2. Patrick R Houlihan
3. Ella Matamala
4. Deny Cabezas-Bratesco
5. Gi Young Lee
6. Ben Cristofori-Armstrong
7. Tanya L Dilan
8. Silvia Sanchez-Martinez
9. Doreen Matthies
10. Rui Yan
11. Zhiheng Yu
12. Dejian Ren
13. Sebastian E Brauchi
14. David E Clapham

• Curated by eLife

  eLife assessment

  The function of specific proteins made by SARS-CoV-1 and SARS-CoV-2 is under debate, with diverging claims previously published regarding the ability of Orf3a proteins from either virus to form ion channels. The authors undertook a thorough characterization of Orf3a from CoV-1 and CoV-2 by combining data from a range of different structural and functional experiments, arguably providing the most compelling evidence to date that Orf3a from viruses is not an ion channel. Instead, the orthologue-specific interaction with a component of a larger protein complex suggests a role of one of the two membrane proteins in the endo-lysosomal pathway. The work is significant from a fundamental science perspective, for its implications for COVID antiviral development strategies, and also for establishing guidelines for future identification of true viral ion channels.

Reviewed by eLife

Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains

1. Artur Meller
2. Jeffrey M Lotthammer
3. Louis G Smith
4. Borna Novak
5. Lindsey A Lee
6. Catherine C Kuhn
7. Lina Greenberg
8. Leslie A Leinwand
9. Michael J Greenberg
10. Gregory R Bowman

• Curated by eLife

  eLife assessment

  This important study presents insights into how conformational dynamics differentially influences drug specificity and affinity in myosin isoforms using computational approaches. The evidence supporting the conclusions is convincing, establishing a relationship between inhibition and protein dynamics using state of the art computational techniques followed by experimental validation. The work will be of broad interest to computational biophysicists and medicinal chemists.

Reviewed by eLife

Dynamics of immune memory and learning in bacterial communities

1. Madeleine Bonsma-Fisher
2. Sidhartha Goyal

• Curated by eLife

  eLife assessment

  In this important work, the authors develop a theory for the co-evolutionary dynamics of bacteria and phages, where the major evolutionary pressure comes from CRISPR-Cas adaptive immunity in bacteria. Through extensive stochastic numerical simulations and analytical calculations, the paper presents a compelling analysis of the emergent properties of immune interactions, in the regime of a single proto-spacer and a single spacer. Some of the trends highlighted by the model are recovered from experimental data. The main results concern how diversity in both phage and bacteria population are linked and are shaped by immunity, and should be of broad interest in immunology.

Reviewed by eLife

Mechanical basis and topological routes to cell elimination

1. Siavash Monfared
2. Guruswami Ravichandran
3. José Andrade
4. Amin Doostmohammadi

• Curated by eLife

  eLife assessment

  In this work, Monfared et al. construct a useful three-dimensional phase-field model for cell layers and use this to investigate the link of extrusion events to defects in cellular arrangement. The extension of existing 2D phase field models to three dimensions is an important contribution of this paper. Here the model is used to study the importance of cell-cell and cell-substrate interaction in extrusion from cell monolayers. Their claim that extrusion events can be distinctly linked to defects in nematic and hexatic orders in the monolayer need to be better justified to be fully convincing.

Reviewed by eLife

Conformational and oligomeric states of SPOP from small-angle X-ray scattering and molecular dynamics simulations

1. F Emil Thomasen
2. Matthew J Cuneo
3. Tanja Mittag
4. Kresten Lindorff-Larsen

• Curated by eLife

  eLife assessment

  In this important paper, the authors have developed an approach for simultaneously optimizing the conformational ensemble and degrees of oligomerization, and this has been tested by applying it to a specific protein (SPOP). Comparison of the quality of fits with different models also provides valuable insights into structural features important to the assembly of oligomers. The approach, presented with compelling experimental support, is potentially applicable to other systems as well.

Reviewed by eLife