2hnd

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spinqualitylabelsall models 2hnd, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of K101E Mutant HIV-1 Reverse Transcriptase in Complex with Nevirapine

Overview

Lys101Glu is a drug resistance mutation in reverse transcriptase, clinically observed in HIV-1 from infected patients treated with the, non-nucleoside inhibitor (NNRTI) drugs nevirapine and efavirenz. In, contrast to many NNRTI resistance mutations, Lys101(p66 subunit) is, positioned at the surface of the NNRTI pocket where it interacts across, the reverse transcriptase (RT) subunit interface with Glu138(p51 subunit)., However, nevirapine contacts Lys101 and Glu138 only indirectly, via water, molecules, thus the structural basis of drug resistance induced by, Lys101Glu is unclear. We have determined crystal structures of, RT(Glu138Lys) and RT(Lys101Glu) in complexes with nevirapine to 2.5 A, allowing the determination of water structure within the NNRTI-binding, pocket, essential for an understanding of nevirapine binding. Both, RT(Glu138Lys) and RT(Lys101Glu) have remarkably similar protein, conformations to wild-type RT, except for significant movement of the, mutated side-chains away from the NNRTI pocket induced by charge, inversion. There are also small shifts in the position of nevirapine for, both mutant structures which may influence ring stacking interactions with, Tyr181. However, the reduction in hydrogen bonds in the, drug-water-side-chain network resulting from the mutated side-chain, movement appears to be the most significant contribution to nevirapine, resistance for RT(Lys101Glu). The movement of Glu101 away from the NNRTI, pocket can also explain the resistance of RT(Lys101Glu) to efavirenz but, in this case is due to a loss of side-chain contacts with the drug., RT(Lys101Glu) is thus a distinctive NNRTI resistance mutant in that it can, give rise to both direct and indirect mechanisms of drug resistance, which, are inhibitor-dependent.

About this Structure

2HND is a Protein complex structure of sequences from Human immunodeficiency virus 1 with PO4, MG and NVP as ligands. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.

Reference

Structural insights into mechanisms of non-nucleoside drug resistance for HIV-1 reverse transcriptases mutated at codons 101 or 138., Ren J, Nichols CE, Stamp A, Chamberlain PP, Ferris R, Weaver KL, Short SA, Stammers DK, FEBS J. 2006 Aug;273(16):3850-60. PMID:16911530

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