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Key HIV Macromolecule Structure Solved
Reviewed December 21, 2012
Researchers at NIAMS (the National Institute of Arthritis and Musculoskeletal and Skin Diseases) and Oxford University have collaborated to determine the three-dimensional structure of Rev (regulator of virus), an essential regulatory macromolecule of HIV. Rev is a protein that escorts viral mRNA molecules out of the infected cell nucleus where they are synthesized into the cytoplasm where they are used to synthesize the building-blocks of a new generation of viral particles. If Rev is absent or is inhibited, an infection cannot proceed.
|HIV-1 Rev protein dimer sandwiched between two antibodies|
|Structure of HIV-1 Rev protein dimer|
Efforts to design drugs that impede Rev's activity have been thwarted by lack of knowledge of Rev's structure. That gap has been filled by the new findings. Protein structures are usually determined by x-ray crystallography; until now, however, Rev's propensity to form irregular or filamentous aggregates has prevented crystallization.
A key step in the new study was the biotechnological feat of generating a "customized" monoclonal antibody that binds to Rev to form a complex that yields well-ordered crystals, whose structure has now been solved. Researchers from the National Cancer Institute and the National Institute of Allergy and Infectious Diseases also participated in this discovery. In its escort duties, some nine copies of Rev co-assemble around a specific motif present on cargo RNAs; the new structure suggests how Rev-Rev interactions may guide the assembly of this complex and identifies key surfaces on Rev which may potentially be targeted in the design of antiviral inhibitors. This study is reported in the current issue of the Proceedings of the National Academy of Sciences USA.
Reference: DiMattia MA, Watts NR, Stahl SJ, Rader C, Wingfield PT, Stuart DI, Steven AC, and Grimes JM. Implications of the HIV-1 Rev dimer structure at 3.2 Å resolution for multimeric binding to the Rev response element. PNAS DOI: 10.1073/pnas.0914946107.