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Verfasst von:Behnam, Mira A. M. [VerfasserIn]   i
Titel:Protein structural heterogeneity
Titelzusatz:a hypothesis for the basis of proteolytic recognition by the main protease of SARS-CoV and SARS-CoV-2
Verf.angabe:Mira A.M. Behnam
E-Jahr:2021
Jahr:20 January 2021
Umfang:8 S.
Teil:volume:182
 year:2021
 pages:177-184
 extent:8
Fussnoten:Gesehen am 12.05.2021
Titel Quelle:Enthalten in: Biochimie
Ort Quelle:Paris [u.a.] : Elsevier, 1971
Jahr Quelle:2021
Band/Heft Quelle:182(2021), Seite 177-184
Abstract:The main protease (Mpro) of SARS-CoV and SARS-CoV-2 is a key enzyme in viral replication and a promising target for the development of antiviral therapeutics. The understanding of this protein is based on a number of observations derived from earlier x-ray structures, which mostly consider substrates or ligands as the main reason behind modulation of the active site. This lead to the concept of substrate-induced subsite cooperativity as an initial attempt to explain the dual binding specificity of this enzyme in recognizing the cleavage sequences at its N- and C-termini, which are important processing steps in obtaining the mature protease. The presented hypothesis proposes that structural heterogeneity is a property of the enzyme, independent of the presence of a substrate or ligand. Indeed, the analysis of Mpro structures of SARS-CoV and SARS-CoV-2 reveals a conformational diversity for the catalytically competent state in ligand-free structures. Variation in the binding site appears to result from flexibility at residues lining the S1 subpocket and segments incorporating methionine 49 and glutamine 189. The structural evidence introduces “structure-based recognition” as a new paradigm in substrate proteolysis by Mpro. In this concept, the binding space in subpockets of the enzyme varies in a non-cooperative manner, causing distinct conformations, which recognize and process different cleavage sites, as the N- and C-termini. Insights into the recognition basis of the protease provide explanation to the ordered processing of cleavage sites. The hypothesis expands the conformational space of the enzyme and consequently opportunities for drug development and repurposing efforts.
DOI:doi:10.1016/j.biochi.2021.01.010
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext ; Verlag: https://doi.org/10.1016/j.biochi.2021.01.010
 Volltext: https://www.sciencedirect.com/science/article/pii/S0300908421000201
 DOI: https://doi.org/10.1016/j.biochi.2021.01.010
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Antiviral drugs
 Conformational selection
 SARS-CoV
 SARS-CoV-2
 Viral protease
K10plus-PPN:1752940733
Verknüpfungen:→ Zeitschrift

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