EMD-32388
Cryo-EM 3D model of the 3-RBD up dimeric spike protein of SARS-CoV2 in the presence of SIH-5
EMD-32388
Single-particle5.41 Å
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Map released: 27/04/2022
Last modified: 10/05/2023
Sample Organism:
Severe acute respiratory syndrome coronavirus 2,
synthetic construct
Sample: SARS-CoV2 spike protein in the presence of peptide SIH-5
Deposition Authors: Khatri B
,
Pramanick I,
Malladi SK
,
Rajmani RS,
Kumar S,
Ghosh P
,
Sengupta N,
Rahisuddin R
,
Kumaran S,
Ringe RP,
Varadarajan R,
Dutta S
,
Chatterjee J
Sample: SARS-CoV2 spike protein in the presence of peptide SIH-5
Deposition Authors: Khatri B
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A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein.
Khatri B
,
Pramanick I,
Malladi SK
,
Rajmani RS,
Kumar S,
Ghosh P
,
Sengupta N,
Rahisuddin R
,
Kumar N,
Kumaran S,
Ringe RP,
Varadarajan R,
Dutta S
,
Chatterjee J
(2022) Nat Chem Biol , 18 , 1046 - 1055
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(2022) Nat Chem Biol , 18 , 1046 - 1055
Abstract:
Protein tertiary structure mimetics are valuable tools to target large protein-protein interaction interfaces. Here, we demonstrate a strategy for designing dimeric helix-hairpin motifs from a previously reported three-helix-bundle miniprotein that targets the receptor-binding domain (RBD) of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Through truncation of the third helix and optimization of the interhelical loop residues of the miniprotein, we developed a thermostable dimeric helix-hairpin. The dimeric four-helix bundle competes with the human angiotensin-converting enzyme 2 (ACE2) in binding to RBD with 2:2 stoichiometry. Cryogenic-electron microscopy revealed the formation of dimeric spike ectodomain trimer by the four-helix bundle, where all the three RBDs from either spike protein are attached head-to-head in an open conformation, revealing a novel mechanism for virus neutralization. The proteomimetic protects hamsters from high dose viral challenge with replicative SARS-CoV-2 viruses, demonstrating the promise of this class of peptides that inhibit protein-protein interaction through target dimerization.
Protein tertiary structure mimetics are valuable tools to target large protein-protein interaction interfaces. Here, we demonstrate a strategy for designing dimeric helix-hairpin motifs from a previously reported three-helix-bundle miniprotein that targets the receptor-binding domain (RBD) of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Through truncation of the third helix and optimization of the interhelical loop residues of the miniprotein, we developed a thermostable dimeric helix-hairpin. The dimeric four-helix bundle competes with the human angiotensin-converting enzyme 2 (ACE2) in binding to RBD with 2:2 stoichiometry. Cryogenic-electron microscopy revealed the formation of dimeric spike ectodomain trimer by the four-helix bundle, where all the three RBDs from either spike protein are attached head-to-head in an open conformation, revealing a novel mechanism for virus neutralization. The proteomimetic protects hamsters from high dose viral challenge with replicative SARS-CoV-2 viruses, demonstrating the promise of this class of peptides that inhibit protein-protein interaction through target dimerization.