3DOK
Crystal structure of K103N mutant HIV-1 reverse transcriptase in complex with GW678248.
Summary for 3DOK
| Entry DOI | 10.2210/pdb3dok/pdb |
| Related | 3DLE 3DLG 3DM2 3DMJ 3DOL |
| Descriptor | Reverse transcriptase/ribonuclease H, p51 RT, PHOSPHATE ION, ... (5 entities in total) |
| Functional Keywords | hiv-1 reverse transcriptase, aids, nnrti, gw678248, drug resistance, hydrolase, transferase |
| Biological source | Human immunodeficiency virus type 1 (HIV-1) More |
| Cellular location | Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P04585 P04585 |
| Total number of polymer chains | 2 |
| Total formula weight | 116577.18 |
| Authors | Chamberlain, P.P.,Ren, J.,Stammers, D.K. (deposition date: 2008-07-04, release date: 2008-08-12, Last modification date: 2024-11-13) |
| Primary citation | Ren, J.,Chamberlain, P.P.,Stamp, A.,Short, S.A.,Weaver, K.L.,Romines, K.R.,Hazen, R.,Freeman, A.,Ferris, R.G.,Andrews, C.W.,Boone, L.,Chan, J.H.,Stammers, D.K. Structural basis for the improved drug resistance profile of new generation benzophenone non-nucleoside HIV-1 reverse transcriptase inhibitors. J.Med.Chem., 51:5000-5008, 2008 Cited by PubMed Abstract: Owing to the emergence of resistant virus, next generation non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) with improved drug resistance profiles have been developed to treat HIV infection. Crystal structures of HIV-1 RT complexed with benzophenones optimized for inhibition of HIV mutants that were resistant to the prototype benzophenone GF128590 indicate factors contributing to the resilience of later compounds in the series (GW4511, GW678248). Meta-substituents on the benzophenone A-ring had the designed effect of inducing better contacts with the conserved W229 while reducing aromatic stacking interactions with the highly mutable Y181 side chain, which unexpectedly adopted a "down" position. Up to four main-chain hydrogen bonds to the inhibitor also appear significant in contributing to resilience. Structures of mutant RTs (K103N, V106A/Y181C) with benzophenones showed only small rearrangements of the NNRTIs relative to wild-type. Hence, adaptation to a mutated NNRTI pocket by inhibitor rearrangement appears less significant for benzophenones than other next-generation NNRTIs. PubMed: 18665583DOI: 10.1021/jm8004493 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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