Quenching protein dynamics interferes with HIV capsid maturation

Mingzhang Wang, Caitlin M. Quinn, Juan R. Perilla (), Huilan Zhang, Randall Shirra, Guangjin Hou, In-Ja Byeon, Christopher L. Suiter, Sherimay Ablan, Emiko Urano, Theodore J. Nitz, Christopher Aiken, Eric O. Freed, Peijun Zhang, Klaus Schulten, Angela M. Gronenborn () and Tatyana Polenova ()
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Mingzhang Wang: Department of Chemistry and Biochemistry, University of Delaware
Caitlin M. Quinn: Department of Chemistry and Biochemistry, University of Delaware
Juan R. Perilla: Department of Chemistry and Biochemistry, University of Delaware
Huilan Zhang: Department of Chemistry and Biochemistry, University of Delaware
Randall Shirra: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Guangjin Hou: Department of Chemistry and Biochemistry, University of Delaware
In-Ja Byeon: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Christopher L. Suiter: Department of Chemistry and Biochemistry, University of Delaware
Sherimay Ablan: HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute
Emiko Urano: HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute
Theodore J. Nitz: DFH Pharma
Christopher Aiken: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Eric O. Freed: HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute
Peijun Zhang: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Klaus Schulten: University of Illinois, Theoretical and Computational Biophysics Group
Angela M. Gronenborn: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Tatyana Polenova: Department of Chemistry and Biochemistry, University of Delaware

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01856-y

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