Dataset Information

Structural basis for mouse receptor recognition by SARS-CoV-2 omicron variant.

ABSTRACT: The sudden emergence and rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant has raised questions about its animal reservoir. Here, we investigated receptor recognition of the omicron's receptor-binding domain (RBD), focusing on four of its mutations (Q493R, Q498R, N501Y, and Y505H) surrounding two mutational hotspots. These mutations have variable effects on the RBD's affinity for human angiotensin-converting enzyme 2 (ACE2), but they all enhance the RBD's affinity for mouse ACE2. We further determined the crystal structure of omicron RBD complexed with mouse ACE2. The structure showed that all four mutations are viral adaptations to mouse ACE2: three of them (Q493R, Q498R, and Y505H) are uniquely adapted to mouse ACE2, whereas the other one (N501Y) is adapted to both human ACE2 and mouse ACE2. These data reveal that the omicron RBD was well adapted to mouse ACE2 before omicron started to infect humans, providing insight into the potential evolutionary origin of the omicron variant.

SUBMITTER: Zhang W

PROVIDER: S-EPMC9636943 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Structural basis for mouse receptor recognition by SARS-CoV-2 omicron variant.

Zhang Wei W Shi Ke K Geng Qibin Q Ye Gang G Aihara Hideki H Li Fang F

Proceedings of the National Academy of Sciences of the United States of America 20221018 44

The sudden emergence and rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant has raised questions about its animal reservoir. Here, we investigated receptor recognition of the omicron's receptor-binding domain (RBD), focusing on four of its mutations (Q493R, Q498R, N501Y, and Y505H) surrounding two mutational hotspots. These mutations have variable effects on the RBD's affinity for human angiotensin-converting enzyme 2 (ACE2), but they all enhance the ...[more]

PMID: 36256797

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Project description:The highly contagious and fast-spreading omicron variant of SARS-CoV-2 infects the respiratory tracts efficiently. The receptor-binding domain (RBD) of the omicron spike protein recognizes human angiotensin-converting enzyme 2 (ACE2) as its receptor and plays a critical role in the tissue tropism of SARS-CoV-2. Here, we showed that the omicron RBD (strain BA.1) binds to ACE2 more strongly than does the prototypic RBD from the original Wuhan strain. We also measured how individual omicron mutations affect ACE2 binding. We further determined the crystal structure of the omicron RBD (engineered to facilitate crystallization) complexed with ACE2 at 2.6 Å. The structure shows that omicron mutations caused significant structural rearrangements of two mutational hot spots at the RBD/ACE2 interface, elucidating how each omicron mutation affects ACE2 binding. The enhanced ACE2 binding by the omicron RBD may facilitate the omicron variant's infection of the respiratory tracts where ACE2 expression level is low. Our study provides insights into the receptor recognition and tissue tropism of the omicron variant. IMPORTANCE Despite the scarcity of the SARS-CoV-2 receptor-human angiotensin-converting enzyme 2 (ACE2)-in the respiratory tract, the omicron variant efficiently infects the respiratory tract, causing rapid and widespread infections of COVID-19. The omicron variant contains extensive mutations in the receptor-binding domain (RBD) of its spike protein that recognizes human ACE2. Here, using a combination of biochemical and X-ray crystallographic approaches, we showed that the omicron RBD binds to ACE2 with enhanced affinity and also elucidated the role of each of the omicron mutations in ACE2 binding. The enhanced ACE2 binding by the omicron RBD may contribute to the omicron variant's new viral tropism in the respiratory tract despite the low level of ACE2 expression in the tissue. These findings help us to understand tissue tropism of the omicron variant and shed light on the molecular evolution of SARS-CoV-2.

Project description:Understanding the evolutionary strategies of the SARS-CoV-2 omicron variant is crucial for comprehending the COVID-19 pandemic and preventing future coronavirus pandemics. In this study, we determined the crystal structures of the receptor-binding domains (RBDs) from currently circulating omicron subvariants XBB.1 and XBB.1.5 (also the emerging XBB.1.9.1), each complexed with human ACE2. We studied how individual RBD residues evolved structurally in omicron subvariants, specifically how they adapted to human ACE2. Our findings revealed that residues 493 and 496, which exhibited good human ACE2 adaptation in pre-omicron variants, evolved to poor adaptation in early omicron subvariants (but with good adaption to mouse ACE2) and then reverted to good adaptation in recent omicron subvariants. This result is consistent with the hypothesis that non-human animals facilitated the evolution of early omicron subvariants. Additionally, residue 486, which exhibited good human ACE2 adaptation in early omicron subvariants, evolved to poor adaptation in later omicron subvariants and then returned to good adaptation in recent omicron subvariants. This result is consistent with the hypothesis that immune evasion facilitated the evolution of later omicron subvariants. Thus, our study suggests that both non-human animals and immune evasion may have contributed to driving omicron evolution at different stages of the pandemic. IMPORTANCE The sudden emergence and continued evolution of the SARS-CoV-2 omicron variant have left many mysteries unanswered, such as the origin of early omicron subvariants and the factors driving omicron evolution. To address these questions, we studied the crystal structures of human ACE2-bound receptor-binding domains (RBDs) from omicron subvariants XBB.1 and XBB.1.5 (XBB.1.9.1). Our in-depth structural analysis sheds light on how specific RBD mutations adapt to either human or mouse ACE2 and suggests non-human animals and immune evasion may have influenced omicron evolution during different stages of the pandemic. These findings provide valuable insights into the mechanisms underlying omicron evolution, deepen our understanding of the COVID-19 pandemic, and have significant implications for preventing future coronavirus pandemics.

Dataset Information

Structural basis for mouse receptor recognition by SARS-CoV-2 omicron variant.

Publications

Structural basis for mouse receptor recognition by SARS-CoV-2 omicron variant.

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