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Flap structure within receptor binding domain of SARS-CoV-2 spike periodically obstructs hACE2 Binding subdomain bearing similarities to HIV-1 protease flap

The SARS-CoV-2 prefusion spike protein is characterized by a high degree of flexibility and temporal transformations associated with its multifunctional behavior. In this study, we have examined the dynamics of the Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein in detail. Its primary,...

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Autor principal: Peters, Michael H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9517965/
https://www.ncbi.nlm.nih.gov/pubmed/36171252
http://dx.doi.org/10.1038/s41598-022-20656-z
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author Peters, Michael H.
author_facet Peters, Michael H.
author_sort Peters, Michael H.
collection PubMed
description The SARS-CoV-2 prefusion spike protein is characterized by a high degree of flexibility and temporal transformations associated with its multifunctional behavior. In this study, we have examined the dynamics of the Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein in detail. Its primary, binding subdomain with human Angiotensin Covering Enzyme II includes a highly conspicuous flap or loop that is part of a beta hairpin loop structural motif. Dynamic details of the RBD obtained through RMSF and Order Parameter calculations are consistent with structural details including the stability of “glue” points or dominant interaction energy residues of the RBD in the Up and Down states with its neighboring N-terminal domain (NTD) protomer. The RBD flap in the Up state protomer periodically obstructs the binding site on an approximate 70 ns time interval and is reminiscent of an HIV-1 protease polypeptide flap that opens and closes to modulate that enzymes activity. No claim is made here regarding the possible modulating role of the flap; however, the flap may be a potential site for therapeutic targeting aimed at keeping it in the closed state, as previously demonstrated in the inhibition of the HIV-1 protease polypeptide. The RBD primary binding subdomain is further shown to have not only similar dynamics but, also, an approximate 30% sequence similarity to the HIV-1 protease polypeptide.
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spelling pubmed-95179652022-09-29 Flap structure within receptor binding domain of SARS-CoV-2 spike periodically obstructs hACE2 Binding subdomain bearing similarities to HIV-1 protease flap Peters, Michael H. Sci Rep Article The SARS-CoV-2 prefusion spike protein is characterized by a high degree of flexibility and temporal transformations associated with its multifunctional behavior. In this study, we have examined the dynamics of the Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein in detail. Its primary, binding subdomain with human Angiotensin Covering Enzyme II includes a highly conspicuous flap or loop that is part of a beta hairpin loop structural motif. Dynamic details of the RBD obtained through RMSF and Order Parameter calculations are consistent with structural details including the stability of “glue” points or dominant interaction energy residues of the RBD in the Up and Down states with its neighboring N-terminal domain (NTD) protomer. The RBD flap in the Up state protomer periodically obstructs the binding site on an approximate 70 ns time interval and is reminiscent of an HIV-1 protease polypeptide flap that opens and closes to modulate that enzymes activity. No claim is made here regarding the possible modulating role of the flap; however, the flap may be a potential site for therapeutic targeting aimed at keeping it in the closed state, as previously demonstrated in the inhibition of the HIV-1 protease polypeptide. The RBD primary binding subdomain is further shown to have not only similar dynamics but, also, an approximate 30% sequence similarity to the HIV-1 protease polypeptide. Nature Publishing Group UK 2022-09-28 /pmc/articles/PMC9517965/ /pubmed/36171252 http://dx.doi.org/10.1038/s41598-022-20656-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Peters, Michael H.
Flap structure within receptor binding domain of SARS-CoV-2 spike periodically obstructs hACE2 Binding subdomain bearing similarities to HIV-1 protease flap
title Flap structure within receptor binding domain of SARS-CoV-2 spike periodically obstructs hACE2 Binding subdomain bearing similarities to HIV-1 protease flap
title_full Flap structure within receptor binding domain of SARS-CoV-2 spike periodically obstructs hACE2 Binding subdomain bearing similarities to HIV-1 protease flap
title_fullStr Flap structure within receptor binding domain of SARS-CoV-2 spike periodically obstructs hACE2 Binding subdomain bearing similarities to HIV-1 protease flap
title_full_unstemmed Flap structure within receptor binding domain of SARS-CoV-2 spike periodically obstructs hACE2 Binding subdomain bearing similarities to HIV-1 protease flap
title_short Flap structure within receptor binding domain of SARS-CoV-2 spike periodically obstructs hACE2 Binding subdomain bearing similarities to HIV-1 protease flap
title_sort flap structure within receptor binding domain of sars-cov-2 spike periodically obstructs hace2 binding subdomain bearing similarities to hiv-1 protease flap
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9517965/
https://www.ncbi.nlm.nih.gov/pubmed/36171252
http://dx.doi.org/10.1038/s41598-022-20656-z
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