2BAN
Crystal structure of HIV-1 reverse transcriptase (RT) in complex with JANSSEN-R157208
Summary for 2BAN
Entry DOI | 10.2210/pdb2ban/pdb |
Related | 1S6P 1S6Q 1SV5 2B5J 2BE2 |
Descriptor | Reverse transcriptase P66 subunit, Reverse transcriptase P51 subunit, MANGANESE (II) ION, ... (5 entities in total) |
Functional Keywords | aids, hiv, drug design, reverse transcriptase, rt, protein-inhibitor complex, transferase |
Biological source | Human immunodeficiency virus 1 More |
Cellular location | Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366 P03366 |
Total number of polymer chains | 2 |
Total formula weight | 115166.11 |
Authors | Das, K.,Arnold, E. (deposition date: 2005-10-14, release date: 2005-12-06, Last modification date: 2023-08-23) |
Primary citation | Himmel, D.M.,Das, K.,Clark Jr., A.D.,Hughes, S.H.,Benjahad, A.,Oumouch, S.,Guillemont, J.,Coupa, S.,Poncelet, A.,Csoka, I.,Meyer, C.,Andries, K.,Nguyen, C.H.,Grierson, D.S.,Arnold, E. Crystal Structures for HIV-1 Reverse Transcriptase in Complexes with Three Pyridinone Derivatives: A New Class of Non-Nucleoside Inhibitors Effective against a Broad Range of Drug-Resistant Strains. J.Med.Chem., 48:7582-7591, 2005 Cited by PubMed Abstract: In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT mutations that cause resistance to NNRTIs in the clinic. We report X-ray crystal structures for RT complexed with three different pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 A resolution, respectively. All three ligands exhibit nanomolar or subnanomolar inhibitory activity against wild-type RT, but varying activities against drug-resistant mutants. R165481 and R221239 differ from most NNRTIs in that binding does not involve significant contacts with Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom on the pyridinone ring of both inhibitors that interacts with the main-chain carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially improves the activity of the compound against wild-type RT (and several mutants) and provides a way to generate novel inhibitors that could interact with conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239, there is a flexible linker to a furan ring that permits interactions with Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory activity of R221239 against the HIV-1 strains that carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations. PubMed: 16302798DOI: 10.1021/jm0500323 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.95 Å) |
Structure validation
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