Mingzhang Wang, Caitlin M. Quinn, Juan R. Perilla, Huilan Zhang, Randall Shirra
Jr., 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.
Quenching protein dynamics interferes with HIV capsid maturation.
Nature Communications, 8:1779, 2017.
(PMC: PMC5701193)
WANG2017
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.
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