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Nat Commun. 2017 Nov 24;8(1):1779. doi: 10.1038/s41467-017-01856-y.

Quenching protein dynamics interferes with HIV capsid maturation.

Author information

1
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA.
2
Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA.
3
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA. jperilla@udel.edu.
4
University of Illinois, Theoretical and Computational Biophysics Group, Urbana, IL, 61801, USA. jperilla@udel.edu.
5
Department of Structural Biology, University of Pittsburgh School of Medicine, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA.
6
HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA.
7
DFH Pharma, Gaithersburg, MD, 20886, USA.
8
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
9
Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, OX3 7BN, UK.
10
University of Illinois, Theoretical and Computational Biophysics Group, Urbana, IL, 61801, USA.
11
Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA. amg100@pitt.edu.
12
Department of Structural Biology, University of Pittsburgh School of Medicine, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA. amg100@pitt.edu.
13
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA. tpolenov@udel.edu.
14
Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA. tpolenov@udel.edu.

Abstract

Maturation of HIV-1 particles encompasses a complex morphological transformation of Gag via an orchestrated series of proteolytic cleavage events. A longstanding question concerns the structure of the C-terminal region of CA and the peptide SP1 (CA-SP1), which represents an intermediate during maturation of the HIV-1 virus. By integrating NMR, cryo-EM, and molecular dynamics simulations, we show that in CA-SP1 tubes assembled in vitro, which represent the features of an intermediate assembly state during maturation, the SP1 peptide exists in a dynamic helix-coil equilibrium, and that the addition of the maturation inhibitors Bevirimat and DFH-055 causes stabilization of a helical form of SP1. Moreover, the maturation-arresting SP1 mutation T8I also induces helical structure in SP1 and further global dynamical and conformational changes in CA. Overall, our results show that dynamics of CA and SP1 are critical for orderly HIV-1 maturation and that small molecules can inhibit maturation by perturbing molecular motions.

PMID:
29176596
PMCID:
PMC5701193
DOI:
10.1038/s41467-017-01856-y
[Indexed for MEDLINE]
Free PMC Article

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