8gb0

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[8gb0]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8GB0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GB0 FirstGlance]. <br>
<table><tr><td colspan='2'>[[8gb0]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8GB0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GB0 FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8gb0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gb0 OCA], [https://pdbe.org/8gb0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gb0 RCSB], [https://www.ebi.ac.uk/pdbsum/8gb0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gb0 ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.1&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8gb0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gb0 OCA], [https://pdbe.org/8gb0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gb0 RCSB], [https://www.ebi.ac.uk/pdbsum/8gb0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gb0 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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SARS-CoV-2 variants bearing complex combinations of mutations have been associated with increased transmissibility, COVID-19 severity, and immune escape. S:D614G may have facilitated emergence of such variants since they appeared after S:D614G had gone to fixation. To test this hypothesis, Spike sequences from an immunocompromised individual with prolonged infection, and from the major SARS-CoV-2 variants of concern, were reverted to the ancestral S:D614. In all cases, infectivity of the revertants was compromised. Rare SARS-CoV-2 lineages that lack S:D614G were identified and the infectivity of these was dependent upon S:Q613H or S:H655Y. Notably, Gamma and Omicron variants possess both S:D614G and S:H655Y, each of which contributed to infectivity of these variants. All three mutations, S:Q613H, S:D614G, and S:H655Y, stabilized Spike on virions, consistent with selection of these mutations by a common molecular mechanism. Among sarbecoviruses, S:Q613H, S:D614G, and S:H655Y are only detected in SARS-CoV-2, which uniquely possesses a polybasic S1/S2 cleavage site. Results of genetic and biochemical experiments here demonstrated that S:D614G and S:H655Y are likely adaptations to the cleavage site. CryoEM revealed that both mutations shift the Spike receptor binding domain towards the open conformation required for ACE2-binding and Spikes bearing either S:D614G or S:H655Y spontaneously mimic the smFRET signal that ACE2 induces in the parental molecule. Data from these orthogonal experiments demonstrate that S:D614G and S:H655Y are convergent adaptations to the polybasic S1/S2 cleavage site, which stabilize S1 on the virion in the open RBD conformation that is on-pathway for target cell fusion, and thereby act epistatically to promote the fitness of variants bearing complex combinations of clinically significant mutations. HIGHLIGHTS: S:D614G is ubiquitous among SARS-CoV-2 B-lineage Spikes and is required for infectivity of the main Variants of ConcernIn an example of convergent evolution, rare SARS-CoV-2 A lineage viruses maintained transmission chains in the absence of S:D614G, but were instead dependent upon S:Q613H or S:H655YS:D614G and S:H655Y are both adaptations to the polybasic S1/S2 cleavage siteIncreased infectivity of S:D614G and S:H655Y is associated with a more open RBD conformation and increased steady-state levels of virion-associated S1.
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SARS-CoV-2 variants bearing complex combinations of mutations that confer increased transmissibility, COVID-19 severity, and immune escape, were first detected after S:D614G had gone to fixation, and likely originated during persistent infection of immunocompromised hosts. To test the hypothesis that S:D614G facilitated emergence of such variants, S:D614G was reverted to the ancestral sequence in the context of sequential Spike sequences from an immunocompromised individual, and within each of the major SARS-CoV-2 variants of concern. In all cases, infectivity of the S:D614G revertants was severely compromised. The infectivity of atypical SARS-CoV-2 lineages that propagated in the absence of S:D614G was found to be dependent upon either S:Q613H or S:H655Y. Notably, Gamma and Omicron variants possess both S:D614G and S:H655Y, each of which contributed to infectivity of these variants. Among sarbecoviruses, S:Q613H, S:D614G, and S:H655Y are only detected in SARS-CoV-2, which is also distinguished by a polybasic S1/S2 cleavage site. Genetic and biochemical experiments here showed that S:Q613H, S:D614G, and S:H655Y each stabilize Spike on virions, and that they are dispensable in the absence of S1/S2 cleavage, consistent with selection of these mutations by the S1/S2 cleavage site. CryoEM revealed that either S:D614G or S:H655Y shift the Spike receptor binding domain (RBD) towards the open conformation required for ACE2-binding and therefore on pathway for infection. Consistent with this, an smFRET reporter for RBD conformation showed that both S:D614G and S:H655Y spontaneously adopt the conformation that ACE2 induces in the parental Spike. Data from these orthogonal experiments demonstrate that S:D614G and S:H655Y are convergent adaptations to the polybasic S1/S2 cleavage site which stabilize S1 on the virion in the open RBD conformation and act epistatically to promote the fitness of variants bearing complex combinations of clinically significant mutations.
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S:D614G and S:H655Y are gateway mutations that act epistatically to promote SARS-CoV-2 variant fitness.,Yurkovetskiy L, Egri S, Kurhade C, Diaz-Salinas MA, Jaimes JA, Nyalile T, Xie X, Choudhary MC, Dauphin A, Li JZ, Munro JB, Shi PY, Shen K, Luban J bioRxiv. 2023 Mar 31:2023.03.30.535005. doi: 10.1101/2023.03.30.535005. Preprint. PMID:37034621<ref>PMID:37034621</ref>
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S:D614G and S:H655Y are gateway mutations that act epistatically to promote SARS-CoV-2 variant fitness.,Yurkovetskiy L, Egri S, Kurhade C, Diaz-Salinas MA, Jaimes JA, Nyalile T, Xie X, Choudhary MC, Dauphin A, Li JZ, Munro JB, Shi PY, Shen K, Luban J bioRxiv [Preprint]. 2023 Apr 24:2023.03.30.535005. doi: , 10.1101/2023.03.30.535005. PMID:37034621<ref>PMID:37034621</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Current revision

SARS-CoV-2 Spike H655Y variant, One RBD Open

PDB ID 8gb0

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