Structural basis for the different states of the spike protein of SARS-CoV-2 in complex with ACE2.
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ABSTRACT:
SUBMITTER: Yan R
PROVIDER: S-EPMC7972335 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:MOTIVATION:The recent emergence of the novel SARS-coronavirus 2 (SARS-CoV-2) and its international spread pose a global health emergency. The spike (S) glycoprotein binds ACE2 and promotes SARS-CoV-2 entry into host cells. The trimeric S protein binds the receptor using the receptor-binding domain (RBD) causing conformational changes in S protein that allow priming by host cell proteases. Unraveling the dynamic structural features used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal novel therapeutic targets. Using structures determined by X-ray crystallography and cryo-EM, we performed structural analysis and atomic comparisons of the different conformational states adopted by the SARS-CoV-2-RBD. RESULTS:Here, we determined the key structural components induced by the receptor and characterized their intramolecular interactions. We show that ?-helix (polyproline-II) is a predominant structure in the binding interface and in facilitating the conversion to the active form of the S protein. We demonstrate a series of conversions between switch-like ?-helix and ?-strand, and conformational variations in a set of short ?-helices which affect the hinge region. These conformational changes lead to an alternating pattern in conserved disulfide bond configurations positioned at the hinge, indicating a possible disulfide exchange, an important allosteric switch implicated in viral entry of various viruses, including HIV and murine coronavirus. The structural information presented herein enables to inspect and understand the important dynamic features of SARS-CoV-2-RBD and propose a novel potential therapeutic strategy to block viral entry. Overall, this study provides guidance for the design and optimization of structure-based intervention strategies that target SARS-CoV-2. AVAILABILITY:We have implemented the proposed methods in an R package freely available at https://github.com/Grantlab/bio3d. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.
| S-EPMC7558967 | biostudies-literature
Project description: Not available
| EMPIAR-11181 | biostudies-other
Project description:ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to dissociation of ACE2 from its E3 ligase UBR4. Reduction of UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, as well as ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19.
| S-SCDT-EMM-2022-15904 | biostudies-other
Project description:The human ACE2 enzyme serves as a critical first recognition point of coronaviruses, including SARS-CoV-2. In particular, the extracellular domain of ACE2 interacts directly with the S1 tailspike protein of the SARS-CoV-2 virion through a broad protein-protein interface. Although this interaction has been characterized by X-ray crystallography, these structures do not reveal significant differences in the ACE2 structure upon S1 protein binding. In this work, using several all-atom molecular dynamics simulations, we show persistent differences in the ACE2 structure upon binding. These differences are determined with the linear discriminant analysis (LDA) machine learning method and validated using independent training and testing datasets, including long trajectories generated by D. E. Shaw Research on the Anton 2 supercomputer. In addition, long trajectories for 78 potent ACE2-binding compounds, also generated by D. E. Shaw Research, were projected onto the LDA classification vector in order to determine whether the ligand-bound ACE2 structures were compatible with S1 protein binding. This allows us to predict which compounds are "apo-like" versus "complex-like" and to pinpoint long-range ligand-induced allosteric changes in the ACE2 structure.
| S-EPMC8370119 | biostudies-literature
Project description: Not available
| S-BSST649 | biostudies-other
Project description:SARS-CoV-2 entry in human cells is mediated by the interaction between the viral Spike protein and the human ACE2 receptor. This mechanism evolved from the ancestor bat coronavirus and is currently one of the main targets for antiviral strategies. However, there currently exist several Spike protein variants in the SARS-CoV-2 population as the result of mutations, and it is unclear if these variants may exert a specific effect on the affinity with ACE2 which, in turn, is also characterized by multiple alleles in the human population. In the current study, the GBPM analysis, originally developed for highlighting host-guest interaction features, has been applied to define the key amino acids responsible for the Spike/ACE2 molecular recognition, using four different crystallographic structures. Then, we intersected these structural results with the current mutational status, based on more than 295,000 sequenced cases, in the SARS-CoV-2 population. We identified several Spike mutations interacting with ACE2 and mutated in at least 20 distinct patients: S477N, N439K, N501Y, Y453F, E484K, K417N, S477I and G476S. Among these, mutation N501Y in particular is one of the events characterizing SARS-CoV-2 lineage B.1.1.7, which has recently risen in frequency in Europe. We also identified five ACE2 rare variants that may affect interaction with Spike and susceptibility to infection: S19P, E37K, M82I, E329G and G352V.Communicated by Ramaswamy H. Sarma.
| S-EPMC7885719 | biostudies-literature
Project description:The initial step of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) involves the binding of receptor binding domain (RBD) of the spike protein to the angiotensin converting enzyme 2 (ACE2) receptor. Each successive wave of SARS-CoV-2 reports emergence of many new variants, which is associated with mutations in the RBD as well as other parts of the spike protein. These mutations are reported to have enhanced affinity towards the ACE2 receptor as well as are also crucial for the virus transmission. Many computational and experimental studies have demonstrated the effect of individual mutation on the RBD-ACE2 binding. However, the cumulative effect of mutations on the RBD and away from the RBD was not investigated in detail. We report here a comparative analysis on the structural communication and dynamics of the RBD and truncated S1 domain of spike protein in complex with the ACE2 receptor from SARS-CoV-2 wild type and its P.1 variant. Our integrative network and dynamics approaches highlighted a subtle conformational changes in the RBD as well as truncated S1 domain of spike protein at the protein contact level, responsible for the increased affinity with the ACE2 receptor. Moreover, our study also identified the commonalities and differences in the dynamics of the interactions between spike protein of SARS-CoV-2 wild type and its P.1 variant with the ACE2 receptor. Further, our investigation yielded an understanding towards identification of the unique RBD residues crucial for the interaction with the ACE2 host receptor. Overall, the study provides an insight for designing better therapeutics against the circulating P.1 variants as well as other future variants.
| S-EPMC9347910 | biostudies-literature
Project description: Not available
| EMPIAR-11180 | biostudies-other
Project description: Not available
| EMPIAR-11179 | biostudies-other
Project description: Not available
| EMPIAR-11176 | biostudies-other