Cargando…

The tem­per­ature-dependent conformational ensemble of SARS-CoV-2 main protease (M(pro))

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M(pro), is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of M(pro) were obtained at cryogenic tem­per­ature or...

Descripción completa

Detalles Bibliográficos
Autores principales: Ebrahim, Ali, Riley, Blake T., Kumaran, Desigan, Andi, Babak, Fuchs, Martin R., McSweeney, Sean, Keedy, Daniel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9438506/
https://www.ncbi.nlm.nih.gov/pubmed/36071812
http://dx.doi.org/10.1107/S2052252522007497
_version_ 1784781839543566336
author Ebrahim, Ali
Riley, Blake T.
Kumaran, Desigan
Andi, Babak
Fuchs, Martin R.
McSweeney, Sean
Keedy, Daniel A.
author_facet Ebrahim, Ali
Riley, Blake T.
Kumaran, Desigan
Andi, Babak
Fuchs, Martin R.
McSweeney, Sean
Keedy, Daniel A.
author_sort Ebrahim, Ali
collection PubMed
description The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M(pro), is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of M(pro) were obtained at cryogenic tem­per­ature or room tem­per­ature only. Here we report a series of high-resolution crystal structures of unliganded M(pro) across multiple tem­per­atures from cryogenic to physiological, and another at high humidity. We inter­rogate these data sets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a perturbation-dependent conformational landscape for M(pro), including a mobile zinc ion inter­leaved between the catalytic dyad, mercurial conformational heterogeneity at various sites including a key substrate-binding loop, and a far-reaching intra­molecular network bridging the active site and dimer inter­face. Our results may inspire new strategies for antiviral drug development to aid preparation for future coronavirus pandemics.
format Online
Article
Text
id pubmed-9438506
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher International Union of Crystallography
record_format MEDLINE/PubMed
spelling pubmed-94385062022-09-06 The tem­per­ature-dependent conformational ensemble of SARS-CoV-2 main protease (M(pro)) Ebrahim, Ali Riley, Blake T. Kumaran, Desigan Andi, Babak Fuchs, Martin R. McSweeney, Sean Keedy, Daniel A. IUCrJ Research Papers The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M(pro), is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of M(pro) were obtained at cryogenic tem­per­ature or room tem­per­ature only. Here we report a series of high-resolution crystal structures of unliganded M(pro) across multiple tem­per­atures from cryogenic to physiological, and another at high humidity. We inter­rogate these data sets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a perturbation-dependent conformational landscape for M(pro), including a mobile zinc ion inter­leaved between the catalytic dyad, mercurial conformational heterogeneity at various sites including a key substrate-binding loop, and a far-reaching intra­molecular network bridging the active site and dimer inter­face. Our results may inspire new strategies for antiviral drug development to aid preparation for future coronavirus pandemics. International Union of Crystallography 2022-08-17 /pmc/articles/PMC9438506/ /pubmed/36071812 http://dx.doi.org/10.1107/S2052252522007497 Text en © Ali Ebrahim et al. 2022 https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Ebrahim, Ali
Riley, Blake T.
Kumaran, Desigan
Andi, Babak
Fuchs, Martin R.
McSweeney, Sean
Keedy, Daniel A.
The tem­per­ature-dependent conformational ensemble of SARS-CoV-2 main protease (M(pro))
title The tem­per­ature-dependent conformational ensemble of SARS-CoV-2 main protease (M(pro))
title_full The tem­per­ature-dependent conformational ensemble of SARS-CoV-2 main protease (M(pro))
title_fullStr The tem­per­ature-dependent conformational ensemble of SARS-CoV-2 main protease (M(pro))
title_full_unstemmed The tem­per­ature-dependent conformational ensemble of SARS-CoV-2 main protease (M(pro))
title_short The tem­per­ature-dependent conformational ensemble of SARS-CoV-2 main protease (M(pro))
title_sort tem­per­ature-dependent conformational ensemble of sars-cov-2 main protease (m(pro))
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9438506/
https://www.ncbi.nlm.nih.gov/pubmed/36071812
http://dx.doi.org/10.1107/S2052252522007497
work_keys_str_mv AT ebrahimali thetemperaturedependentconformationalensembleofsarscov2mainproteasempro
AT rileyblaket thetemperaturedependentconformationalensembleofsarscov2mainproteasempro
AT kumarandesigan thetemperaturedependentconformationalensembleofsarscov2mainproteasempro
AT andibabak thetemperaturedependentconformationalensembleofsarscov2mainproteasempro
AT fuchsmartinr thetemperaturedependentconformationalensembleofsarscov2mainproteasempro
AT mcsweeneysean thetemperaturedependentconformationalensembleofsarscov2mainproteasempro
AT keedydaniela thetemperaturedependentconformationalensembleofsarscov2mainproteasempro
AT ebrahimali temperaturedependentconformationalensembleofsarscov2mainproteasempro
AT rileyblaket temperaturedependentconformationalensembleofsarscov2mainproteasempro
AT kumarandesigan temperaturedependentconformationalensembleofsarscov2mainproteasempro
AT andibabak temperaturedependentconformationalensembleofsarscov2mainproteasempro
AT fuchsmartinr temperaturedependentconformationalensembleofsarscov2mainproteasempro
AT mcsweeneysean temperaturedependentconformationalensembleofsarscov2mainproteasempro
AT keedydaniela temperaturedependentconformationalensembleofsarscov2mainproteasempro