7a91 | pdb_00007a91
Dissociated S1 domain of SARS-CoV-2 Spike bound to ACE2 (Non-Uniform Refinement)
Structural highlights
FunctionACE2_HUMAN Carboxypeptidase which converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator. Also able to hydrolyze apelin-13 and dynorphin-13 with high efficiency. May be an important regulator of heart function. In case of human coronaviruses SARS and HCoV-NL63 infections, serve as functional receptor for the spike glycoprotein of both coronaviruses.[1] [2] [3] Publication Abstract from PubMedSARS-CoV-2 infection is initiated by virus binding to ACE2 cell surface receptors(1-4), followed by fusion of virus and cell membranes to release the virus genome into the cell. Both receptor binding and membrane fusion activities are mediated by the virus Spike glycoprotein, S(5-7). As with other class I membrane fusion proteins, S is post-translationally cleaved, in this case by furin, into S1 and S2 components that remain associated following cleavage(8-10). Fusion activation following receptor binding is proposed to involve the exposure of a second proteolytic site (S2'), cleavage of which is required for the fusion peptide release(11,12). We have investigated the binding of ACE2 to the furin-cleaved form of SARS-CoV-2 S by cryoEM. We classify ten different molecular species including the unbound, closed spike trimer, the fully open ACE2-bound trimer, and dissociated monomeric S1 bound to ACE2. The ten structures describe ACE2 binding events which destabilise the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts and un-shields the trimeric S2 core, priming fusion activation and dissociation of ACE2-bound S1 monomers. The structures also reveal refolding of an S1 subdomain following ACE2 binding, that disrupts interactions with S2, notably involving Asp614(13-15), leading to destabilisation of the structure of S2 proximal to the secondary (S2') cleavage site. Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion.,Benton DJ, Wrobel AG, Xu P, Roustan C, Martin SR, Rosenthal PB, Skehel JJ, Gamblin SJ Nature. 2020 Sep 17. pii: 10.1038/s41586-020-2772-0. doi:, 10.1038/s41586-020-2772-0. PMID:32942285[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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