Structure of unliganded HIV-1 reverse transcriptase at 2.7 å resolution: implications of conformational changes for polymerization and inhibition mechanisms
| Autor: | Edward Arnold, Y. Hsiou, Jianping Ding, S.H. Hughes, Arthur D. Clark, Kalyan Das |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Anti-HIV Agents
Protein Conformation Stereochemistry drug design Molecular Sequence Data polymerase structure Thumb Cleavage (embryo) Biopolymers Protein structure X-Ray Diffraction Structural Biology medicine non-nucleoside inhibition mechanism Binding site RNase H Molecular Biology Polymerase Binding Sites biology Chemistry Nucleotidyltransferase HIV Reverse Transcriptase Reverse transcriptase body regions AIDS medicine.anatomical_structure HIV-1 biology.protein Reverse Transcriptase Inhibitors mechanism of polymerization |
| Zdroj: | Structure. 4(7):853-860 |
| ISSN: | 0969-2126 |
| DOI: | 10.1016/s0969-2126(96)00091-3 |
| Popis: | Background: HIV-1 reverse transcriptase (RT) is a major target for anti-HIV drugs. A considerable amount of information about the structure of RT is available, both unliganded and in complex with template-primer or non-nucleoside RT inhibitors (NNRTIs). But significant conformational differences in the p66 polymerase domain among the unliganded structures have complicated the interpretation of these data, leading to different proposals for the mechanisms of polymerization and inhibition. Results We report the structure of an unliganded RT at 2.7 a resolution, crystallized in space group C2 with a crystal packing similar to that of the RT–NNRTI complexes. The p66 thumb subdomain is folded into the DNA-binding cleft. Comparison of the unliganded RT structures with the DNA-bound RT and the NNRTI-bound RT structures reveals that the p66 thumb subdomain can exhibit two different upright conformations. In the DNA-bound RT, the p66 thumb subdomain adopts an upright position that can be described as resulting from a rigid-body rotation of the p66 thumb along the ‘thumb's knuckle' located near residues Trp239 (in strand β 14) and Val317 (in β 15) compared with the thumb position in the unliganded RT structure. NNRTI binding induces an additional hinge movement of the p66 thumb near the thumb's knuckle, causing the p66 thumb to adopt a configuration that is even more extended than in the DNA-bound RT structure. Conclusion The p66 thumb subdomain is extremely flexible. NNRTI binding induces both short-range and long-range structural distortions in several domains of RT, which are expected to alter the position and conformation of the template-primer. These changes may account for the inhibition of polymerization and the alteration of the cleavage specificity of RNase H by NNRTI binding. |
| Databáze: | OpenAIRE |
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