Biochemistry

Targeting an evolutionarily conserved “E-L-L” motif in spike protein to identify a small molecule fusion inhibitor against SARS-CoV-2

1. Indrani Das Jana
2. Prabuddha Bhattacharya
3. Karthick Mayilsamy
4. Saptarshi Banerjee
5. Gourab Bhattacharje
6. Sayan Das
7. Seemanti Aditya
8. Anandita Ghosh
9. Andrew R McGill
10. Syamanthak Srikrishnan
11. Amit Kumar Das
12. Amit Basak
13. Shyam S Mohapatra
14. Bala Chandran
15. Devesh Bhimsaria
16. Subhra Mohapatra
17. Arunava Roy
18. Arindam Mondal

Reviewed by ScreenIT

Molecular docking between human TMPRSS2 and the serine protease Kunitz-type inhibitor rBmTI-A

1. Lívia de Moraes Bomediano Camillo
2. Sergio Daishi Sasaki

Reviewed by ScreenIT

Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain

1. Atefeh Rafiei
2. Sofía Cruz Tetlalmatzi
3. Claire H Edrington
4. Linda Lee
5. D Alex Crowder
6. Daniel J Saltzberg
7. Andrej Sali
8. Gary Brouhard
9. David C Schriemer

• Curated by eLife

  Evaluation Summary:

  Rafiei et al. investigate the molecular architecture of an important neuronal microtubule-associated protein, doublecortin, bound to the microtubule by integrating data from chemical cross-linking experiments with available crystallographic and cryo-EM structures. They present an appealing model of microtubule-mediated self-association of doublecortin; however, they do not perform any additional assays to support the functional relevance of this model. In addition, there are limitations to the used method in resolving structural details. The manuscript will be relevant for biologists with an interest in microtubule formation and to researchers who apply different structural biology tools to study the organization of large biomolecular assemblies.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Reviewed by eLife

Crystal structures and fragment screening of SARS-CoV-2 NSP14 reveal details of exoribonuclease activation and mRNA capping and provide starting points for antiviral drug development

1. Nergis Imprachim
2. Yuliana Yosaatmadja
3. Joseph A Newman

Reviewed by ScreenIT

Crystal structures of bacterial small multidrug resistance transporter EmrE in complex with structurally diverse substrates

1. Ali A Kermani
2. Olive E Burata
3. B Ben Koff
4. Akiko Koide
5. Shohei Koide
6. Randy B Stockbridge

• Curated by eLife

  Evaluation Summary:

  E. coli EmrE and other members of the SMR family of transporters utilize the proton motive force to pump out a broad spectrum of antibiotics, thereby contributing to multi-drug resistance. Here, a new multipurpose crystallization chaperone is used to determine the structure of EmrE in apo form and in complex with various substrates. The strength of the manuscript is in the description of six new structures of EmrE at a resolution sufficient for building an atomic model and understanding how the antimicrobial agents bind, allowing robust conclusions to be drawn regarding the molecular details of binding of the antimicrobial agents. The report will be of interest to both those studying antibiotic resistance and those studying transporters.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Reviewed by eLife

Determinants of trafficking, conduction, and disease within a K+ channel revealed through multiparametric deep mutational scanning

1. Willow Coyote-Maestas
2. David Nedrud
3. Yungui He
4. Daniel Schmidt

• Curated by eLife

  Evaluation Summary:

  This is a tour de force for mutagenesis and analysis of an ion channel protein, using a straightforward method the authors have developed for the comprehensive functional analysis of a deep mutational library. The approach introduced here will not only be of broad interest to the ion channel community, but it will also serve as a roadmap for performing similar studies on other proteins. The authors demonstrate the usefulness of this method by defining the functional domains of Kir2.1, thereby rediscovering known disease causing mutants, and highlighting a number of mutations with similar phenotypes that may also result in disease phenotypes.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Reviewed by eLife

Discovery of Potent Pyrazoline‐Based Covalent SARS‐CoV‐2 Main Protease Inhibitors**

1. Patrick Moon
2. Charlotte M. Zammit
3. Qian Shao
4. Dustin Dovala
5. Lydia Boike
6. Nathaniel J. Henning
7. Mark Knapp
8. Jessica N. Spradlin
9. Carl C. Ward
10. Helene Wolleb
11. Daniel Fuller
12. Gabrielle Blake
13. Jason P. Murphy
14. Feng Wang
15. Yipin Lu
16. Stephanie A. Moquin
17. Laura Tandeske
18. Matthew J. Hesse
19. Jeffrey M. McKenna
20. John A. Tallarico
21. Markus Schirle
22. F. Dean Toste
23. Daniel K. Nomura

Reviewed by ScreenIT

Zinc pyrithione is a potent inhibitor of PL ^Pro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication

1. Jerneja Kladnik
2. Ana Dolinar
3. Jakob Kljun
4. David Perea
5. Judith Grau-Expósito
6. Meritxell Genescà
7. Marko Novinec
8. Maria J. Buzon
9. Iztok Turel

Reviewed by ScreenIT

Inhibitory proteins block substrate access by occupying the active site cleft of Bacillus subtilis intramembrane protease SpoIVFB

1. Sandra Olenic
2. Lim Heo
3. Michael Feig
4. Lee Kroos

• Curated by eLife

  Evaluation Summary:

  A member of a large class of metalloproteases with representatives in mammals as well as bacteria, its status as a multipass membrane protein has made illuminating the molecular basis of SpoIVFB inhibition challenging. In this study, Olenic and colleagues combine genetics, cross-linking, and co-evolutionary analysis to develop a structural model of interaction between SpoIVFB and its inhibitors SpoIVFA and BofA. Given the conservation and importance of this family of metalloproteases, this work should have broad impact, influencing our understanding of the regulation of this class of proteins across the tree of life.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)

Reviewed by eLife

Emergent properties of a mitotic Kif18b-MCAK-EB network

1. Toni McHugh
2. Julie P.I. Welburn

• Curated by eLife

  Evaluation Summary:

  The authors investigate the mechanisms underlying the regulation of microtubule dynamics and length regulation in cells. Understanding how microtubule-binding proteins synergize to affect microtubule behavior is important, and resolving the seemingly contradictory effects of Kif18a on microtubules in mitotic cells vs. in vitro microtubule assays is a worthy endeavor. A major conclusion is that on dynamic microtubules, combining EB3, MCAK, and Kif18b increases microtubule catastrophe compared to other single or double protein combinations. This is in principle a new and interesting finding, but additional evidence would help to more strongly support this conclusion.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Reviewed by eLife