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Title: X-ray crystal structures of native HIV-1 capsid protein reveal conformational variability

Journal Article · · Science
 [1];  [2];  [3];  [4];  [5];  [6]
  1. Univ. of Missouri, Columbia, MO (United States). Christopher S. Bond Life Sciences Center. Dept. of Chemistry
  2. Univ. of Missouri, Columbia, MO (United States). Christopher S. Bond Life Sciences Center. School of Medicine. Dept. of Molecular Microbiology and Immunology
  3. National Cancer Inst., Frederick, MD (United States). Center for Cancer Research. Basic Research Lab.
  4. Univ. of Missouri, Columbia, MO (United States). Dept. of Chemistry. Dept. of Biochemistry
  5. Univ. of Virginia, Charlottesville, VA (United States). School of Medicine. Dept. of Molecular Physiology and Biological Physics
  6. Univ. of Missouri, Columbia, MO (United States). Christopher S. Bond Life Sciences Center. School of Medicine. Dept. of Molecular Microbiology and Immunology. Dept. of Biochemistry

The detailed molecular interactions between native HIV-1 capsid protein (CA) hexamers that shield the viral genome and proteins have been elusive. In this paper, we report crystal structures describing interactions between CA monomers related by sixfold symmetry within hexamers (intrahexamer) and threefold and twofold symmetry between neighboring hexamers (interhexamer). The structures describe how CA builds hexagonal lattices, the foundation of mature capsids. Lattice structure depends on an adaptable hydration layer modulating interactions among CA molecules. Disruption of this layer alters interhexamer interfaces, highlighting an inherent structural variability. A CA-targeting antiviral affects capsid stability by binding across CA molecules and subtly altering interhexamer interfaces remote to the ligand-binding site. Finally, inherent structural plasticity, hydration layer rearrangement, and effector binding affect capsid stability and have functional implications for the retroviral life cycle.

Research Organization:
Univ. of Missouri, Columbia, MO (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health (NIH) (United States)
Contributing Organization:
National Cancer Inst., Frederick, MD (United States); Univ. of Virginia, Charlottesville, VA (United States)
Grant/Contract Number:
AC02-05CH11231; AI112417; AI120860; GM103368; AI076119; AI099284; AI100890; GM066087
OSTI ID:
1214294
Journal Information:
Science, Vol. 349, Issue 6243; ISSN 0036-8075
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 169 works
Citation information provided by
Web of Science

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Cited By (55)

Fast Magic-Angle Spinning 19 F NMR Spectroscopy of HIV-1 Capsid Protein Assemblies journal October 2018
Fast Magic-Angle Spinning 19 F NMR Spectroscopy of HIV-1 Capsid Protein Assemblies journal October 2018
Segmental isotopic labeling of HIV-1 capsid protein assemblies for solid state NMR journal January 2018
Accuracy and precision of protein structures determined by magic angle spinning NMR spectroscopy: for some ‘with a little help from a friend’ journal March 2019
Expression, Purification and Characterization of Hiv-1 Capsid Precursor Protein p41 journal March 2018
Multiple Roles of HIV-1 Capsid during the Virus Replication Cycle journal April 2019
Structural biology of supramolecular assemblies by magic-angle spinning NMR spectroscopy journal January 2017
HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis journal August 2016
Physical properties of the HIV-1 capsid from all-atom molecular dynamics simulations journal July 2017
HIV-1 assembly, release and maturation journal June 2015
Restriction of HIV-1 and other retroviruses by TRIM5 journal July 2019
Anti-virus reagents targeting the capsid protein assembly journal January 2019
Discovery of novel 1,4-disubstituted 1,2,3-triazole phenylalanine derivatives as HIV-1 capsid inhibitors journal January 2019
Complex-type N -glycans on VSV-G pseudotyped HIV exhibit ‘tough’ sialic and ‘brittle’ mannose self-adhesions journal January 2019
Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation journal December 2015
Dynamic regulation of HIV-1 capsid interaction with the restriction factor TRIM5α identified by magic-angle spinning NMR and molecular dynamics simulations journal October 2018
High-resolution structures of HIV-1 Gag cleavage mutants determine structural switch for virus maturation journal September 2018
Structure and architecture of immature and mature murine leukemia virus capsids journal November 2018
HIV-1 uncoats in the nucleus near sites of integration journal February 2020
Nucleic acid–induced dimerization of HIV-1 Gag protein journal September 2019
Structure of Drosophila melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag journal January 2020
Conformational plasticity of a native retroviral capsid revealed by x-ray crystallography journal June 2015
An atomic model of HIV-1 capsid-SP1 reveals structures regulating assembly and maturation journal July 2016
The structure and flexibility of conical HIV-1 capsids determined within intact virions journal December 2016
Fullerene Derivatives Strongly Inhibit HIV-1 Replication by Affecting Virus Maturation without Impairing Protease Activity journal July 2016
Capsid-CPSF6 Interaction Is Dispensable for HIV-1 Replication in Primary Cells but Is Selected during Virus Passage In Vivo journal June 2016
A Novel Phenotype Links HIV-1 Capsid Stability to cGAS-Mediated DNA Sensing journal June 2019
PF74 Reinforces the HIV-1 Capsid To Impair Reverse Transcription-Induced Uncoating journal August 2018
PF74 Inhibits HIV-1 Integration by Altering the Composition of the Preintegration Complex journal December 2018
Dimerization of the SP1 Region of HIV-1 Gag Induces a Helical Conformation and Association into Helical Bundles: Implications for Particle Assembly journal December 2015
Identification of a Structural Element in HIV-1 Gag Required for Virus Particle Assembly and Maturation journal October 2018
HIV-1 capsid is involved in post-nuclear entry steps journal April 2016
GS-CA Compounds: First-In-Class HIV-1 Capsid Inhibitors Covering Multiple Grounds journal June 2019
HIV Capsid Inhibitors Beyond PF74 journal October 2019
Are microRNAs Important Players in HIV-1 Infection? An Update journal March 2018
The Conserved Tyr176/Leu177 Motif in the α-Helix 9 of the Feline Immunodeficiency Virus Capsid Protein Is Critical for Gag Particle Assembly journal September 2019
CD4-gp120 interaction interface - a gateway for HIV-1 infection in human: molecular network, modeling and docking studies text January 2016
Crystal structure of an HIV assembly and maturation switch journal July 2016
MxB Restricts HIV-1 by Targeting the Tri-hexamer Interface of the Viral Capsid journal August 2019
CD4- gp120 interaction interface - a gateway for HIV-1 infection in human: molecular network, modeling and docking studies journal September 2016
High-resolution structures of HIV-1 Gag cleavage mutants determine structural switch for virus maturation text January 2018
CD4-gp120 interaction interface - a gateway for HIV-1 infection in human: molecular network, modeling and docking studies text January 2016
Structure of Drosophila melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag. text January 2020
Cryo-electron microscopy and single molecule fluorescent microscopy detect CD4 receptor induced HIV size expansion prior to cell entry journal December 2015
All-Atom Molecular Dynamics of Virus Capsids as Drug Targets journal May 2016
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Structure of FIV capsid C-terminal domain demonstrates lentiviral evasion of genetic fragility by coevolved substitutions journal April 2016
Analysis of the functional compatibility of SIV capsid sequences in the context of the FIV gag precursor journal May 2017
Structure of Drosophila melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag. text January 2020
Comparison of Biochemical Properties of HIV-1 and HIV-2 Capsid Proteins journal June 2017
Role for Gag-CA Interdomain Linker in Primate Lentiviral Replication journal August 2019
Properties and Functions of Feline Immunodeficiency Virus Gag Domains in Virion Assembly and Budding journal May 2018
HIV Capsid and Integration Targeting journal January 2021
Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors journal February 2021
Closing the net on retroviruses journal July 2016

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