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Recognition of HIV‐inactivating peptide triazoles by the recombinant soluble Env trimer, BG505 SOSIP.664
Author(s) -
Acharya Kriti,
Rashad Adel A.,
Moraca Francesca,
Klasse Per Johan,
Moore John P.,
Abrams Cameron,
Chaiken Irwin
Publication year - 2017
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25238
Subject(s) - trimer , pharmacophore , chemistry , peptide , protein subunit , recombinant dna , plasma protein binding , biophysics , stereochemistry , microbiology and biotechnology , biochemistry , biology , dimer , organic chemistry , gene
Peptide triazole (PT) antagonists interact with gp120 subunits of HIV‐1 Env trimers to block host cell receptor interactions, trigger gp120 shedding, irreversibly inactivate virus and inhibit infection. Despite these enticing functions, understanding the structural mechanism of PT‐Env trimer encounter has been limited. In this work, we combined competition interaction analysis and computational simulation to demonstrate PT binding to the recombinant soluble trimer, BG505 SOSIP.664, a stable variant that resembles native virus spikes in binding to CD4 receptor as well as known conformationally‐dependent Env antibodies. Binding specificity and computational modeling fit with encounter through complementary PT pharmacophore Ile‐triazolePro‐Trp interaction with a 2‐subsite cavity in the Env gp120 subunit of SOSIP trimer similar to that in monomeric gp120. These findings argue that PTs are able to recognize and bind a closed prefusion state of Env trimer upon HIV‐1 encounter. The results provide a structural model of how PTs exert their function on virion trimeric spike protein and a platform to inform future antagonist design. Proteins 2017; 85:843–851. © 2016 Wiley Periodicals, Inc.