Abstract
The emergence of SARS-CoV-2 Kappa and Beta variants with enhanced transmissibility and resistance to neutralizing antibodies has created new challenges for the control of the ongoing COVID-19 pandemic. Understanding the structural nature of Kappa and Beta spike (S) proteins and their association with ACE2 is of significant importance. Here we present two cryo-EM structures for each of the Kappa and Beta spikes in the open and open-prone transition states. Compared with wild-type (WT) or G614 spikes, the two variant spikes appear more untwisted/open especially for Beta, and display a considerable population shift towards the open state as well as more pronounced conformational dynamics. Moreover, we capture four conformational states of the S-trimer/ACE2 complex for each of the two variants, revealing an enlarged conformational landscape for the Kappa and Beta S-ACE2 complexes and pronounced population shift towards the three RBDs up conformation. These results implicate that the mutations in Kappa and Beta may modify the kinetics of receptor binding and viral fusion to improve virus fitness. Combined with biochemical analysis, our structural study shows that the two variants are enabled to efficiently interact with ACE2 receptor despite their sensitive ACE2 binding surface is modified to escape recognition by some potent neutralizing MAbs. Our findings shed new light on the pathogenicity and immune evasion mechanism of the Beta and Kappa variants.
Highlights
The emergence of SARS-CoV-2 Kappa and Beta variants with enhanced transmissibility and resistance to neutralizing antibodies has created new challenges for the control of the ongoing COVID-19 pandemic
We present cryo-EM structures of the S trimer of the SARS-CoV-2 Kappa and Beta variants in the open or transition state for each variant at the resolution of 3.2–3.6 Å, revealing their unique conformational dynamics potentially related to enhanced virus fitness, and altered antigenic surfaces permitting immune escape
Our biolayer interferometry (BLI) results showed that the KD values for WT, G614, Kappa, and Beta S were 104, Architecture and conformational dynamics of the Kappa variant S trimer
Summary
The emergence of SARS-CoV-2 Kappa and Beta variants with enhanced transmissibility and resistance to neutralizing antibodies has created new challenges for the control of the ongoing COVID-19 pandemic. We capture four conformational states of the S-trimer/ACE2 complex for each of the two variants, revealing an enlarged conformational landscape for the Kappa and Beta S-ACE2 complexes and pronounced population shift towards the three RBDs up conformation These results implicate that the mutations in Kappa and Beta may modify the kinetics of receptor binding and viral fusion to improve virus fitness. We present cryo-EM structures of the S trimer of the SARS-CoV-2 Kappa and Beta variants in the open or transition state for each variant at the resolution of 3.2–3.6 Å, revealing their unique conformational dynamics potentially related to enhanced virus fitness, and altered antigenic surfaces permitting immune escape. Our BLI data are consistent with the S/ACE2 affinity results for Beta/Kappa variants reported recently[29,30,45,46]
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