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Theoretical and Computational Biophysics Group - 'Structural Mechanisms of HIV-1 Capsid Assembly, Maturation and Host Cell Restriction '

Event Type
Klaus Schulten
3269 Beckman Institute, 405 N. Mathews Ave
Mar 25, 2013   3:00 pm  
Professor Peijun Zhang, Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Nancy Mallon

Mature HIV-1 particles contain a conical-shaped capsid that encloses the viral RNA genome and performs essential functions in the virus life cycle. In mature virion, the assembled capsid structure is best described by a fullerene cone model that is made up from a hexameric lattice containing hexameric and pentameric capsid protein (CA). We obtained a cryo-EM structure of HIV-1 capsid assembly at 9  resolution. The density map clearly delineates all the α-helical motifs within the structure. The structure allowed unambiguous modeling and refinement by large scale molecular dynamic simulation, resulting in an all-atom model of the capsid assembly including 13 million atoms. The model revealed new hydrophobic interactions at the inter-subunit trimer interface. Further, cryoEM structural analysis of immature intermediate CA-NC assemblies revealed a marked conformational difference at this trimer interface compared to mature CA assemblies. This difference was verified via analyses of engineered disulfide crosslinking of in vitro assemblies and HIV-1 viral particles, suggesting an important role of the trimer interface in HIV-1 maturation. Using cryoEM, combined with mutagenesis and chemical cross-linking, we further investigated the direct interactions between HIV-1 CA assemblies and a host restriction factor TRIM5αrh

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