Distant residues modulate conformational opening in SARS-CoV-2 spike protein


Posted: 2021-10-07 19:00:00
Proc Natl Acad Sci U S A . 2021 Oct 26;118(43):e2100943118. doi: 10.1073/pnas.2100943118. Epub 2021 Oct 6. Affiliations Expand Affiliations 1 Department of Chemistry, University of California, Irvine, CA 92697. 2 School of Biotechnology, International University, Vietnam National University, Ho Chi Minh City, Vietnam 70000. 3 Department of Chemistry, University of California, Irvine, CA 92697; andricio@uci.edu. 4 Department of Physics and Astronomy, University of California, Irvine, CA 92697. Item in Clipboard Dhiman Ray et al. Proc Natl Acad Sci U S A. 2021. Show details Display options Display options Format Proc Natl Acad Sci U S A . 2021 Oct 26;118(43):e2100943118. doi: 10.1073/pnas.2100943118. Epub 2021 Oct 6. Affiliations 1 Department of Chemistry, University of California, Irvine, CA 92697. 2 School of Biotechnology, International University, Vietnam National University, Ho Chi Minh City, Vietnam 70000. 3 Department of Chemistry, University of California, Irvine, CA 92697; andricio@uci.edu. 4 Department of Physics and Astronomy, University of California, Irvine, CA 92697. Item in Clipboard CiteDisplay options Display options Format Abstract Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) involves the attachment of the receptor-binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down-to-up conformational change in the spike protein, the change that presents the RBD to the receptor. To date, computational and experimental studies that search for therapeutics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and is therefore a hotspot for drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. This allows for a deeper understanding of the underlying molecular recognition events and prediction of the highest-effect key mutations in distant, allosteric sites, with implications for therapeutics. Also, these sites can appear in emerging mutants with possibly higher transmissibility and virulence, and preidentifying them can give clues for designing pan-coronavirus vaccines against future outbreaks. Our model, based on time-lagged independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD opening. Residues involved in the most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predicted ab initio from our model. Conversely, broad-spectrum therapeutics like drugs and monoclonal antibodies can target these key distant-but-conserved regions of the spike protein. Keywords: COVID-19; molecular biophysics; molecular dynamics; statistical mechanics; virus structure. Copyright © 2021 the Author(s). Published by PNAS. References Zhou P., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273. Lu R., et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet. 2020;395:565–574. Ou X., et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun.. 2020;11:1620. Tai W., et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell. Mol. Immunol.. 2020;17:613–620. Koyama T., Platt D., Parida L.. Variant analysis of SARS-CoV-2 genomes. Bull. World Health Organ.. 2020;98:495–504. Show all 85 references [x] Cite Copy Format: Send To [x]

参考サイト PubMed: covid-19



バイオクイックニュース日本語版:COVID-19特集

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8月 05, 2020 バイオアソシエイツ

コウモリのウイルス耐性と長寿命が、新型コロナウイルスへのヒントを提供するとの展望が発表された

コウモリは、ヒトに影響を与える多くの致命的なウイルス(エボラ出血熱、狂犬病、そして最近では COVID-19 を引き起こすコロナウイルスのSARS-CoV-2など)に対し、耐性があると考えられている。 ヒトはこれらの病原体で有害な症状を経験するが、コウモリはウイルスに著しく耐えることができ、さらに、同じサイズの陸上哺乳類よりもはるかに長く生きる。コウモリの寿命とウイルス耐性の秘密は何か?…

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