Crystal structures of HIV-1 RT inhibitor complexes: 'second generation' NNRTIs, efavirenz and S-1153 (AG1549), and NNRTI- and NRTI-resistant mutant forms
Originally Published on September 2, 1999
J Ren, C Nichols, S Shrot, K Weaver, J Lennerstrand, B Larder, DI Stuart and DK Stammers
ABSTRACT: Aim: To understand the structural basis of drug resistance mechanisms for HIV reverse transcriptase inhibitors.
Methods: In order to delineate some of the structural features important for the improved resistance profile of 'second generation' non-nucleoside reverse transcriptase inhibitors (NNRTI) we have determined we have determined structures of reverse transcriptase with efavirenz, UC-781 and S-1153 (AG1549). Additionally we have determined the structures of eight different NNRTI-resistant mutants in complexes with inhibitors. We have been using X-ray crystallographic methods to determine many of these structures at high resolution, for example, efavirenz (2.5 Å), S-1153 (2.5 Å), TN-651+K103N (2.3 Å). This allows full refinement in order to produce accurate atomic models.
Results: The crystallographic results imply a combination of structural features may be important for second generation inhibitors. These include small non-aromatic constituents at the sub-pocket adjacent to Tyr181 and Tyr188 as well as main-chain hydrogen bonding. Structures of Y181C and Y188C RTs show the mutated residues clearly and demonstrate reduced binding of first generation NNRTIs such as nevirapine is due to loss of ring stacking interactions.
Conclusion: In the case of efavirenz and UC-781, such second generation NNRTIs are able to rearrange within mutated drug pockets, thus making them more resilient to the effects of mutations.
