Biophysical Society Thematic Meeting - November 16-20, 2015

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Speaker Abstracts

Structural Basis of HIV-1 Capsid Assembly and Host Cell Interactions Peijun Zhang . University of Pittsburgh School of Medicine, Pittsburgh, USA.

The mature HIV-1 capsid plays a major role in the early stages of HIV-1 replication by protecting the genome from innate immune sensing response and regulating infection by interacting with many host factors including CypA, CPSF6, MxB, TRIM5α and TRIM-Cyp. It contains two structural domains that are connected by a flexible linker and assembles into a distinct cone shaped capsid that encloses the viral genome. We have previously determined the CA tubular assembly to 8 Å using cryoEM and built an all-atom computer model of the complete capsid by large scale molecular dynamics (MD) simulations. Exploiting the recent advance in direct electron detection, we have now obtained the structure of HIV-1 capsid at near-atomic resolution, clearly resolving bulky side chain densities, helix grooves and connecting loops. For the first time, the flexible linker and the major homology region are clearly visualized in an assembly context, providing insights on their critical roles in capsid assembly and maturation. We have also determined the cryoEM structure of the host cell factor CypA in complex with HIV-1 capsid assembly. The density map unexpectedly displays a distinct non-random CypA binding pattern in which CypA bridges two adjacent CA hexamers and wraps selectively along the curved CA array. CryoEM structure-based modeling and large scale all-atoms MD simulations surprisingly reveal that the unique CypA pattern was achieved through an additional uncharacterized novel interface so that a single CypA molecule simultaneously interacts with two CA molecules, therefore, stabilizes and protects the capsid from premature uncoating. Our structure further highlights this novel CypA and CA interface as a potentially attractive therapeutic target for pharmacological intervention.

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