Structural bases for the higher adherence to ACE2 conferred by the SARS‐CoV‐2 spike Q498Y substitution. Issue 9 (25th August 2022)

• Record Type: Journal Article
• Authors: Erausquin, Elena; Glaser, Fabian; Fernández-Recio, Juan; López-Sagaseta, Jacinto
• Is Part Of: Acta crystallographica. Volume 78:Issue 9(2022)
• Page Start: 1156
• Page End: 1170
• Publication Date: 2022-08-25
• Subjects: SARS‐CoV‐2 -- COVID‐19 -- X‐ray structure -- spike protein Q498Y mutation -- binding affinity -- spike protein receptor binding domain -- RBD–ACE2 complex -- ACE2 receptor; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; Molecular biology -- Periodicals; Molecular structure -- Periodicals; Biomolecules -- Structure -- Periodicals; Cytology -- Periodicals; Biomolecules -- Structure; Crystallography; Cytology; Molecular biology; Molecular structure; X-ray crystallography; Periodicals; 548
• DOI: 10.1107/S2059798322007677
• Languages: English
• ISSNs: 2059-7983

Abstract

Abstract : The structural bases underpinning the higher affinity for the human receptor ACE2 conferred by a naturally occurring mutation (Q498Y) in the SARS‐CoV‐2 spike receptor‐binding domain are described. Abstract : A remarkable number of SARS‐CoV‐2 variants and other as yet unmonitored lineages harbor amino‐acid substitutions with the potential to modulate the interface between the spike receptor‐binding domain (RBD) and its receptor ACE2. The naturally occurring Q498Y substitution, which is present in currently circulating SARS‐CoV‐2 variants, has drawn the attention of several investigations. While computational predictions and in vitro binding studies suggest that Q498Y increases the binding affinity of the spike protein for ACE2, experimental in vivo models of infection have shown that a triple mutant carrying the Q498Y replacement is fatal in mice. To accurately characterize the binding kinetics of the RBD Q498Y–ACE2 interaction, biolayer interferometry analyses were performed. A significant enhancement of the RBD–ACE2 binding affinity relative to a reference SARS‐CoV‐2 variant of concern carrying three simultaneous replacements was observed. In addition, the RBD Q498Y mutant bound to ACE2 was crystallized. Compared with the structure of its wild‐type counterpart, the RBD Q498Y–ACE2 complex reveals the conservation of major hydrogen‐bond interactions and a more populated, nonpolar set of contacts mediated by the bulky side chain of Tyr498 that collectively lead to this increase in binding affinity. In summary, these studies contribute to a deeper understanding of the impact of a relevant mutation present in currently circulating SARS‐CoV‐2 variants which might lead to stronger host–pathogen interactions.