Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 15, Pages 8233-8238Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.150220297
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- NIGMS NIH HHS [GM56531, P01 GM056531] Funding Source: Medline
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Insolubility of full-length HIV-1 integrase (IN) limited previous structure analyses to individual domains, By introducing five point mutations, we engineered a more soluble IN that allowed us to generate multidomain HIV-1 IN crystals. The first multidomain HIV-1 IN structure is reported. It incorporates the catalytic core and C-terminal domains (residues 52-288). The structure resolved to 2.8 Angstrom is a Y-shaped dimer, Within the dimer, the catalytic core domains form the only dimer interface, and the C-terminal domains are located 55 Angstrom apart, A 26-aa alpha-helix, alpha 6, links the C-terminal domain to the catalytic core. A kink in one of the two alpha 6 helices occurs near a known proteolytic site, suggesting that it may act as a flexible elbow to reorient the domains during the integration process. Two proteins that bind DNA in a sequence-independent manner are structurally homologous to the HIV-1 IN C-terminal domain, suggesting a similar protein-DNA interaction in which the IN C-terminal domain may serve to bind, bend, and orient viral DNA during integration, A strip of positively charged amino acids contributed by both monomers emerges from each active site of the dimer, suggesting a minimally dimeric platform for binding each viral DNA end. The crystal structure of the isolated catalytic core domain (residues 52-210), independently determined at 1.6-Angstrom resolution, is identical to the core domain within the two-domain 52-288 structure.
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