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Publication Abstract from PubMed

The capsid (CA) protein plays crucial roles in HIV infection and replication, essential to viral maturation. The absence of high-resolution structural data on unassembled CA hinders the development of antivirals effective in inhibiting assembly. Unlike enzymes that have targetable, functional substrate-binding sites, the CA does not have a known site that affects catalytic or other innate activity, which can be more readily targeted in drug development efforts. We report the crystal structure of the HIV-1 CA, revealing the domain organization in the context of the wild-type full-length (FL) unassembled CA. The FL CA adopts an antiparallel dimer configuration, exhibiting a domain organization sterically incompatible with capsid assembly. A small compound, generated in situ during crystallization, is bound tightly at a hinge site ("H site"), indicating that binding at this interdomain region stabilizes the ADP conformation. Electron microscopy studies on nascent crystals reveal both dimeric and hexameric lattices coexisting within a single condition, in agreement with the interconvertibility of oligomeric forms and supporting the feasibility of promoting assembly-incompetent dimeric states. Solution characterization in the presence of the H-site ligand shows predominantly unassembled dimeric CA, even under conditions that promote assembly. Our structure elucidation of the HIV-1 FL CA and characterization of a potential allosteric binding site provides three-dimensional views of an assembly-defective conformation, a state targeted in, and thus directly relevant to, inhibitor development. Based on our findings, we propose an unprecedented means of preventing CA assembly, by "conformationally trapping" CA in assembly-incompetent conformational states induced by H-site binding.

Structure of the HIV-1 full-length capsid protein in a conformationally trapped unassembled state induced by small-molecule binding.,Du S, Betts L, Yang R, Shi H, Concel J, Ahn J, Aiken C, Zhang P, Yeh JI J Mol Biol. 2011 Feb 25;406(3):371-86. doi: 10.1016/j.jmb.2010.11.027. Epub 2010 , Dec 10. PMID:21146540^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.