Issue Date: June 22, 2009
Building HIV's Curvaceous Coat
To reproduce, human immunodeficiency virus must assemble a new coat, or capsid, to package its RNA genome and deliver it to cells. In work that could aid discovery of anti-HIV drugs that block capsid assembly, researchers have now captured the first high-resolution structures of the capsid's basic building block, the CA protein hexamer, and have uncovered new information about how the hexamer flexes to create the curvy cone-shaped capsids.
The work was carried out by Owen Pornillos and Barbie K. Ganser-Pornillos in the lab of cell biologist and physiologist Mark Yeager of Scripps Research Institute and the University of Virginia and coworkers (Cell, DOI: 10.1016/j.cell.2009.04.063).
HIV's capsid is composed of about 250 CA hexamers and 12 CA pentamers—about 1,500 monomeric CA proteins in all. The multimers interact noncovalently to form the shell's curved surface.
Each CA protein's N-terminal domain (NTD) and C-terminal domain (CTD) are flexibly linked to one another. Six NTDs form the rigid core of hexameric CA, and six CTDs form the hexamer's much more flexible outer ring. Dimeric interactions between CTDs of neighboring hexamers hold the capsid together.
Previous studies have yielded structures of the individual domains, the NTD hexamer, and the single CA protein, but not of CA hexamers. These had not yielded to high-resolution structural analysis because they couldn't be crystallized.
Guided by previous electron cryomicroscopy studies, Yeager and coworkers engineered the CA protein to be stable, soluble, and amenable to crystallization. The team then obtained X-ray structures of the engineered protein at atomic (2 Å) resolution.
The structures reveal that interdomain flexibility and mobility of the outer ring enable the hexamer to assemble and give rise to the capsid's curvy shape.
The work "certainly provides new insight into the molecular details of capsid assembly," says Ian A. Taylor, a molecular structure specialist at the National Institute for Medical Research, in Mill Hill, England. "We had little idea of molecular details of the NTD-CTD interface."
The new research "not only provides these details but also confirms the idea that interdomain CTD-CTD and CTD-NTD flexibility abounds and, importantly, likely directs capsid shell curvature," Taylor explains.
In view of the essential role of capsid formation in the HIV life cycle, small-molecule inhibitors of capsid assembly are being sought as potential anti-HIV or AIDS medications. None has been developed yet, but two inhibitors have been found to impede capsid assembly. The new study helps clarify their mechanisms of action and could therefore aid the development of assembly-inhibiting drugs.
Taylor points out that some natural cellular restriction factors—proteins that inhibit retroviral infection—target the same hexameric lattice as assembly inhibitors do, and he notes that structural studies aimed at understanding the specificity of such interactions could also drive future capsid-inhibitor drug discovery.
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