Structural basis for the role of the K65R mutation in HIV-1 reverse transcriptase polymerization, excision antagonism, and tenofovir resistance

Kalyan Das, Rajiv P. Bandwar, Kirsten L. White, Joy Y. Feng, Stefan G. Sarafianos, Steven Tuske, Xiongying Tu, Arthur D. Clark, Paul L. Boyer, Xiaorong Hou, Barbara L. Gaffney, Roger A. Jones, Michael D. Miller, Stephen H. Hughes, Eddy Arnold

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

K65R is a primary reverse transcriptase (RT) mutation selected in human immunodeficiency virus type 1-infected patients taking antiretroviral regimens containing tenofovir disoproxil fumarate or other nucleoside analog RT drugs. We determined the crystal structures of K65R mutant RT crosslinked to double-stranded DNA and in complexes with tenofovir diphosphate (TFV-DP) or dATP. The crystals permit substitution of TFV-DP with dATP at the dNTP-binding site. The guanidinium planes of the arginines K65R and Arg72 were stacked to form a molecular platform that restricts the conformational adaptability of both of the residues, which explains the negative effects of the K65R mutation on nucleotide incorporation and on excision. Furthermore, the guanidinium planes of K65R and Arg72 were stacked in two different rotameric conformations in TFV-DP- and dATP-bound structures that may help explain how K65R RT discriminates the drug from substrates. These K65R-mediated effects onRTstructure and function help us to visualize the complex interaction with other key nucleotide RT drug resistance mutations, such as M184V, L74V, and thymidine analog resistance mutations.

Original languageEnglish (US)
Pages (from-to)35092-35100
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number50
DOIs
StatePublished - Dec 11 2009

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