1S6Q

CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE (RT) IN COMPLEX WITH JANSSEN-R147681

Summary for 1S6Q

• Entry DOI: 10.2210/pdb1s6q/pdb
• Related: 1DLO 1HNI 1HNV 1S6P 1S9E 1S9G 1SUQ 1SV5 1TVR 2HMI
• Descriptor: POL polyprotein [Contains: Reverse transcriptase], 4-[4-(2,4,6-TRIMETHYL-PHENYLAMINO)-PYRIMIDIN-2-YLAMINO]-BENZONITRILE (3 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: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03366 P03366
• Total number of polymer chains: 2
• Total formula weight: 115112.13

Authors

Das, K.,Arnold, E. (deposition date: 2004-01-26, release date: 2004-05-11, Last modification date: 2024-02-14)

Primary citation

Das, K.,Clark, A.D.,Lewi, P.J.,Heeres, J.,De Jonge, M.R.,Koymans, L.M.,Vinkers, H.M.,Daeyaert, F.,Ludovici, D.W.,Kukla, M.J.,De Corte, B.,Kavash, R.W.,Ho, C.Y.,Ye, H.,Lichtenstein, M.A.,Andries, K.,Pauwels, R.,Boyer, P.L.,Clark, P.,Hughes, S.H.,Janssen, P.A.,Arnold, E.
Roles of Conformational and Positional Adaptability in Structure-Based Design of TMC125-R165335 (Etravirine) and Related Non-nucleoside Reverse Transcriptase Inhibitors That Are Highly Potent and Effective against Wild-Type and Drug-Resistant HIV-1 Variants.
J.Med.Chem., 47:2550-2560, 2004

PubMed Abstract: Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.

PubMed: 15115397
DOI: 10.1021/jm030558s

Experimental method

X-RAY DIFFRACTION (3 Å)