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Title: Structure of the HIV-1 Full-Length Capsid Protein in a Conformationally Trapped Unassembled State Induced by Small-Molecule Binding

Abstract

The capsid (CA) protein plays crucial roles in HIV infection and replication, essential to viral maturation. The absence of high-resolution structural data on unassembled CA hinders the development of antivirals effective in inhibiting assembly. Unlike enzymes that have targetable, functional substrate-binding sites, the CA does not have a known site that affects catalytic or other innate activity, which can be more readily targeted in drug development efforts. We report the crystal structure of the HIV-1 CA, revealing the domain organization in the context of the wild-type full-length (FL) unassembled CA. The FL CA adopts an antiparallel dimer configuration, exhibiting a domain organization sterically incompatible with capsid assembly. A small compound, generated in situ during crystallization, is bound tightly at a hinge site ('H site'), indicating that binding at this interdomain region stabilizes the ADP conformation. Electron microscopy studies on nascent crystals reveal both dimeric and hexameric lattices coexisting within a single condition, in agreement with the interconvertibility of oligomeric forms and supporting the feasibility of promoting assembly-incompetent dimeric states. Solution characterization in the presence of the H-site ligand shows predominantly unassembled dimeric CA, even under conditions that promote assembly. Our structure elucidation of the HIV-1 FL CA and characterization ofmore » a potential allosteric binding site provides three-dimensional views of an assembly-defective conformation, a state targeted in, and thus directly relevant to, inhibitor development. Based on our findings, we propose an unprecedented means of preventing CA assembly, by 'conformationally trapping' CA in assembly-incompetent conformational states induced by H-site binding.« less

Authors:
; ; ; ; ; ; ; ;  [1]
  1. UNCO
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHER U.S. STATESNIH
OSTI Identifier:
1033807
Resource Type:
Journal Article
Journal Name:
J. Mol. Biol.
Additional Journal Information:
Journal Volume: 406; Journal Issue: (3) ; 02, 2011; Journal ID: ISSN 0022-2836
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Du, Shoucheng, Betts, Laurie, Yang, Ruifeng, Shi, Haibin, Concel, Jason, Ahn, Jinwoo, Aiken, Christopher, Zhang, Peijun, Yeh, Joanne I., Pitt), and Vanderbilt). Structure of the HIV-1 Full-Length Capsid Protein in a Conformationally Trapped Unassembled State Induced by Small-Molecule Binding. United States: N. p., 2018. Web. doi:10.1016/j.jmb.2010.11.027.
Du, Shoucheng, Betts, Laurie, Yang, Ruifeng, Shi, Haibin, Concel, Jason, Ahn, Jinwoo, Aiken, Christopher, Zhang, Peijun, Yeh, Joanne I., Pitt), & Vanderbilt). Structure of the HIV-1 Full-Length Capsid Protein in a Conformationally Trapped Unassembled State Induced by Small-Molecule Binding. United States. https://doi.org/10.1016/j.jmb.2010.11.027
Du, Shoucheng, Betts, Laurie, Yang, Ruifeng, Shi, Haibin, Concel, Jason, Ahn, Jinwoo, Aiken, Christopher, Zhang, Peijun, Yeh, Joanne I., Pitt), and Vanderbilt). 2018. "Structure of the HIV-1 Full-Length Capsid Protein in a Conformationally Trapped Unassembled State Induced by Small-Molecule Binding". United States. https://doi.org/10.1016/j.jmb.2010.11.027.
@article{osti_1033807,
title = {Structure of the HIV-1 Full-Length Capsid Protein in a Conformationally Trapped Unassembled State Induced by Small-Molecule Binding},
author = {Du, Shoucheng and Betts, Laurie and Yang, Ruifeng and Shi, Haibin and Concel, Jason and Ahn, Jinwoo and Aiken, Christopher and Zhang, Peijun and Yeh, Joanne I. and Pitt) and Vanderbilt)},
abstractNote = {The capsid (CA) protein plays crucial roles in HIV infection and replication, essential to viral maturation. The absence of high-resolution structural data on unassembled CA hinders the development of antivirals effective in inhibiting assembly. Unlike enzymes that have targetable, functional substrate-binding sites, the CA does not have a known site that affects catalytic or other innate activity, which can be more readily targeted in drug development efforts. We report the crystal structure of the HIV-1 CA, revealing the domain organization in the context of the wild-type full-length (FL) unassembled CA. The FL CA adopts an antiparallel dimer configuration, exhibiting a domain organization sterically incompatible with capsid assembly. A small compound, generated in situ during crystallization, is bound tightly at a hinge site ('H site'), indicating that binding at this interdomain region stabilizes the ADP conformation. Electron microscopy studies on nascent crystals reveal both dimeric and hexameric lattices coexisting within a single condition, in agreement with the interconvertibility of oligomeric forms and supporting the feasibility of promoting assembly-incompetent dimeric states. Solution characterization in the presence of the H-site ligand shows predominantly unassembled dimeric CA, even under conditions that promote assembly. Our structure elucidation of the HIV-1 FL CA and characterization of a potential allosteric binding site provides three-dimensional views of an assembly-defective conformation, a state targeted in, and thus directly relevant to, inhibitor development. Based on our findings, we propose an unprecedented means of preventing CA assembly, by 'conformationally trapping' CA in assembly-incompetent conformational states induced by H-site binding.},
doi = {10.1016/j.jmb.2010.11.027},
url = {https://www.osti.gov/biblio/1033807}, journal = {J. Mol. Biol.},
issn = {0022-2836},
number = (3) ; 02, 2011,
volume = 406,
place = {United States},
year = {Fri Dec 07 00:00:00 EST 2018},
month = {Fri Dec 07 00:00:00 EST 2018}
}