Summary information and primary citation
- PDB-id
-
6ik9;
DSSR-derived features in text and
JSON formats
- Class
- transferase-DNA
- Method
- X-ray (2.435 Å)
- Summary
- Hiv-1 reverse transcriptase with
q151m-g112s-d113a-y115f-f116y-f160l-i159l:DNA:dgtp ternary
complex
- Reference
-
Yasutake Y, Hattori SI, Tamura N, Matsuda K, Kohgo S,
Maeda K, Mitsuya H (2019): "Active-site
deformation in the structure of HIV-1 RT with
HBV-associated septuple amino acid substitutions
rationalizes the differential susceptibility of HIV-1 and
HBV against 4'-modified nucleoside RT inhibitors."
Biochem. Biophys. Res. Commun.,
509, 943-948. doi: 10.1016/j.bbrc.2019.01.026.
- Abstract
- Nucleoside analogue reverse transcriptase (RT)
inhibitors (NRTIs) are major antiviral agents against
hepatitis B virus (HBV) and human immunodeficiency virus
type-1 (HIV-1). However, the notorious insoluble property
of HBV RT has prevented atomic-resolution structural
studies and rational anti-HBV drug design. Here, we created
HIV-1 RT mutants containing HBV-mimicking sextuple or
septuple amino acid substitutions at the nucleoside-binding
site (N-site) and verified that these mutants retained the
RT activity. The most active RT mutant, HIV-1
RT<sub>7MC</sub>, carrying
Q151M/G112S/D113A/Y115F/F116Y/F160L/I159L was successfully
crystallized, and its three-dimensional structure was
determined in complex with DNA:dGTP/entecavir-triphosphate
(ETV-TP), a potent anti-HBV guanosine analogue RT
inhibitor, at a resolution of 2.43 Å and 2.60 Å,
respectively. The structures reveal significant positional
rearrangements of the amino acid side-chains at the N-site,
elucidating the mechanism underlying the differential
susceptibility of HIV-1 and HBV against recently reported
4'-modified NRTIs.
