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

被引:353
作者
Chen, JCH
Krucinski, J
Miercke, LJW
Finer-Moore, JS
Tang, AH
Leavitt, AD
Stroud, RM [1 ]
机构
[1] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Internal Med, San Francisco, CA 94143 USA
关键词
D O I
10.1073/pnas.150220297
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页码:8233 / 8238
页数:6
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