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2BAN

Crystal structure of HIV-1 reverse transcriptase (RT) in complex with JANSSEN-R157208

Summary for 2BAN
Entry DOI10.2210/pdb2ban/pdb
Related1S6P 1S6Q 1SV5 2B5J 2BE2
DescriptorReverse transcriptase P66 subunit, Reverse transcriptase P51 subunit, MANGANESE (II) ION, ... (5 entities in total)
Functional Keywordsaids, hiv, drug design, reverse transcriptase, rt, protein-inhibitor complex, transferase
Biological sourceHuman immunodeficiency virus 1
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Cellular locationGag-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 chains2
Total formula weight115166.11
Authors
Das, K.,Arnold, E. (deposition date: 2005-10-14, release date: 2005-12-06, Last modification date: 2023-08-23)
Primary citationHimmel, 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: 16302798
DOI: 10.1021/jm0500323
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.95 Å)
Structure validation

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