Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: A model for viral DNA binding

Insolubility of full-length HIV-1 integrase (IN) limited previous structure analyses to individual domains, By introducing five point mutations, we en gineered a more soluble IN that allowed us to generate multidomain HIV-1 IN crystals. The first multidomain HIV-1 IN structure is reported. It incorpo rates the catalytic core and C-terminal domains (residues 52-288). The stru cture resolved to 2.8 Angstrom is a Y-shaped dimer, Within the dimer, the c atalytic core domains form the only dimer interface, and the C-terminal dom ains 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. T wo 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 ami no acids contributed by both monomers emerges from each active site of the dimer, suggesting a minimally dimeric platform for binding each viral DNA e nd. The crystal structure of the isolated catalytic core domain (residues 5 2-210), independently determined at 1.6-Angstrom resolution, is identical t o the core domain within the two-domain 52-288 structure.