6IK9

HIV-1 reverse transcriptase with Q151M/G112S/D113A/Y115F/F116Y/F160L/I159L:DNA:dGTP ternary complex

Summary for 6IK9

• Entry DOI: 10.2210/pdb6ik9/pdb
• Descriptor: HIV-1 reverse transcriptase p66 subunit, HIV-1 reverse transcriptase p51 subunit, DNA/RNA (38-MER), ... (7 entities in total)
• Functional Keywords: hiv-1, hbv, reverse transcriptase, drug resistance, drug sensitivity, entecavir, transferase-dna complex, replication, transferase/dna
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 6
• Total formula weight: 256574.22

Authors

Yasutake, Y.,Hattori, S.I.,Tamura, N.,Maeda, K. (deposition date: 2018-10-15, release date: 2019-01-30, Last modification date: 2023-11-22)

Primary citation

Yasutake, Y.,Hattori, S.I.,Tamura, N.,Matsuda, K.,Kohgo, S.,Maeda, K.,Mitsuya, H.
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, 2019

PubMed 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, 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.

PubMed: 30648556
DOI: 10.1016/j.bbrc.2019.01.026

Experimental method

X-RAY DIFFRACTION (2.435 Å)