EMD-32388

Single-particle
5.41 Å
EMD-32388 Deposition: 15/12/2021
Map released: 27/04/2022
Last modified: 10/05/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

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-particle
5.41 Å
EMD-32388 Deposition: 15/12/2021
Map released: 27/04/2022
Last modified: 10/05/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
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
A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein.
PUBMED: 35654847
DOI: doi:10.1038/s41589-022-01060-0
ISSN: 1552-4469
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.