title: Inhibitor binding alters the directions of domain motions in HIV-1 reverse transcriptase.
abstract: Understanding the molecular mechanisms of HIV-1 reverse transcriptase (RT) action and drug inhibition is essential for designing effective antiretroviral therapies. Although comparisons of the different crystal forms of RT give insights into the flexibility of different domains, a direct computational assessment of the effect of inhibitor binding on the collective dynamics of RT is lacking. A structure-based approach is used here for exploring the dynamics of RT in unliganded and inhibitor-bound forms. Non-nucleoside RT inhibitors (NNRTI) are shown to interfere directly with the global hinge-bending mechanism that controls the cooperative motions of the p66 fingers and thumb subdomains. The net effect of nevirapine binding is to change the direction of domain movements rather than suppress their mobilities. The second generation NNRTI, efavirenz, on the other hand, shows the stronger effect of simultaneously reorienting domain motions and obstructing the p66 thumb fluctuations. A second hinge site controlling the global rotational reorientations of the RNase H domain is identified, which could serve as a target for potential inhibitors of RNase H activity.
authors.affiliation: Center for Computational Biology and Bioinformatics, and Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, Pennsylvania 15213, USA.
authors.forename: N Alpay
authors.initials: NA
authors.lastname: Temiz
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D048588:Benzoxazines; D001665:Binding Sites; D003521:Cyclopropanes; D016503:Drug Delivery Systems; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D009038:Motion; D019829:Nevirapine / Q000737:chemistry / Q000378:metabolism; D010078:Oxazines / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D016914:Ribonuclease H / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D008024:Ligands; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H; C098320:efavirenz