Summary information and primary citation
- PDB-id
-
3jsm;
DSSR-derived features in text and
JSON formats
- Class
- transferase-DNA complex
- Method
- X-ray (3.0 Å)
- Summary
- K65r mutant hiv-1 reverse transcriptase cross-linked to
ds-DNA and complexed with tenofovir-diphosphate as the
incoming nucleotide substrate
- Reference
-
Das K, Bandwar RP, White KL, Feng JY, Sarafianos SG,
Tuske S, Tu X, Clark AD, Boyer PL, Hou X, Gaffney BL,
Jones RA, Miller MD, Hughes SH, Arnold E (2009):
"Structural
basis for the role of the K65r mutation in HIV-1 reverse
transcriptase polymerization, excision antagonism, and
tenofovir resistance." J.Biol.Chem.,
284, 35092-35100. doi: 10.1074/jbc.M109.022525.
- 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 cross-linked 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
Arg(72) 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 Arg(72)
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 on RT structure 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.
