SNAP output for PDB entry 6ika [SNAP web server]

PDB-id

6ika; SNAP-derived features in text and JSON formats; DNAproDB

Class

transferase-DNA

Method

X-ray (2.598 Å)

Summary

Hiv-1 reverse transcriptase with q151m-g112s-d113a-y115f-f116y-f160l-i159l:DNA:entecavir-triphosphate 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_7MC, 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.