Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM

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.

Molecular basis of SARS-CoV-2 Omicron variant receptor engagement and antibody evasion and neutralization

“…2C), displaying an obvious higher one-RBD-up C1 population than that of the Beta/Kappa/Delta variants (C1 population ranges from 8.3% to 14.1%) observed in our recent studies 31,32 . These three variants also showed a C3 state with all-threeup RBDs associated with ACE2 (27.7% to 46.6% populated) 31,32 , not detected here in the Omicron variant, in line with recent preprint reports 16,28,38 . Taken together, the Omicron S trimer exhibits less ability to transform to the more RBD-up C2/C3 states as compared to that of the Beta, Kappa, and Delta VOCs.…”

“…The population distribution between Omicron S-ACE2-C1 and -C2 is about 43.9% versus 56.1% (Fig. 2C), displaying an obvious higher one-RBD-up C1 population than that of the Beta/Kappa/Delta variants (C1 population ranges from 8.3% to 14.1%) observed in our recent studies 31,32 . These three variants also showed a C3 state with all-threeup RBDs associated with ACE2 (27.7% to 46.6% populated) 31,32 , not detected here in the Omicron variant, in line with recent preprint reports 16,28,38 .…”

“…1G). There is no linoleic acid (termed LA) in the Omicron S-open and S-close maps, as in our recent Delta, Kappa, and Beta S structures obtained in the same construction and purification condition 31,32 . LA binding has been detected in the tightly closed WT S trimer structures [33][34][35][36] , and been suggested to lead to more compacted RBDs 33 .…”

“…Noteworthy, the population distribution of the Omicron S-close and S-open is about 61% and 39% (Fig. 1D), respectively, displaying a considerable population distribution shift to the closed state than that of the Kappa and Beta variants S trimer (both around 50%-50% opentransition ratio) or that of the Delta S (75.3%-24.7% open-transition ratio) from our recent studiues 31,32 . Taken together, the Omicron S trimer appears more prone to the closed state and potentially stabilized relative to the counterparts of the G614, Kappa, Beta, and Delta variants.…”

“…1A-B). In contrast to the S trimer of Delta/Beta/Kappa variants 31,32 , the Omicron S-close and S-open structures appear more twisted/compact than their counterpart of the G614 strain (Fig. 1F-G).…”