2BE2

Crystal structure of HIV-1 reverse transcriptase (RT) in complex with R221239

Summary for 2BE2

• Entry DOI: 10.2210/pdb2be2/pdb
• Related: 2B5J 2BAN
• Related PRD ID: PRD_900003
• Descriptor: REVERSE TRANSCRIPTASE P66 SUBUNIT, REVERSE TRANSCRIPTASE P51 SUBUNIT, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: aids, hiv, drug design, reverse transcriptase, rt, protein-inhibitor complex, drug resistance, 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: 116187.79

Authors

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. (deposition date: 2005-10-21, 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

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

Experimental method

X-RAY DIFFRACTION (2.43 Å)