3rd International Workshop on HIV Drug Resistance 2-5 August 1994, Kauai, Hawaii, USA

HIGH RESOLUTION REFINED STRUCTURES OF HIV-1 REVERSE TRANSCRIPTASE-INHIBITOR COMPLEXES: IMPLICATIONS FOR DRUG RESISTANCE

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:29 (abstract no. 28)

D.I. Stuart^†, J.S. Rent^†, R. Esnouf^†, E.Y. Jones^†, C. Ross^*, D. Somers^* and D.K. Stammers^*
†Laboratory of Molecular Biophysics, University of Oxford, Oxford, U.K.; ^*Wellcome Research Laboratories, Beckenham, Kent, U.K.

The aim of the work is to produce a high resolution fully refined X-ray structure of the HIV-1 reverse transcriptase(RT) suitable for use in drug design as well as in the understanding of the structural basis of drug resistance mechanisms. To this end we have obtained crystals of RT complexed with a variety of non-nucleoside inhibitors. Four related crystal forms have been obtained. These are all of space group P2₁2₁2₁ with differing unit cell dimensions. Two of the forms in complex with nevirapine or a nevirapine analogue diffract X-rays to 2.2 Å resolution. Crystals of RT with α-APA and HEPT have also been obtained. The structures have been solved by molecular replacement. Phase refinement has been achieved by cross-averaging between the different crystal forms. This has lead to a refined structure at 2.2 Å with R=O.187. The four inhibitors bind in a common site and adopt very similar overlapping conformations inspite of being chemically different. The location of residues that undergo mutation to give rise to resistance are in close proximity to the inhibitors.

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1994-08-02
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