5XN2

HIV-1 reverse transcriptase Q151M:DNA:dGTP ternary complex

Summary for 5XN2

• Entry DOI: 10.2210/pdb5xn2/pdb
• Related: 4ZHR
• Related PRD ID: PRD_900003
• Descriptor: Pol protein, 38-MER DNA aptamer, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: hiv-1, hbv, reverse transcriptase, drug resistance, drug sensitivity, entecavir, transferase-dna complex, transferase/dna
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 6
• Total formula weight: 257012.52

Authors

Yasutake, Y.,Tamura, N.,Hayashi, H.,Maeda, K. (deposition date: 2017-05-17, release date: 2018-02-07, Last modification date: 2023-11-22)

Primary citation

Yasutake, Y.,Hattori, S.I.,Hayashi, H.,Matsuda, K.,Tamura, N.,Kohgo, S.,Maeda, K.,Mitsuya, H.
HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir.
Sci Rep, 8:1624-1624, 2018

PubMed Abstract: Hepatitis B virus (HBV) reverse transcriptase (RT) is essential for viral replication and is an important drug target. Nonetheless, the notorious insolubility of HBV RT has hindered experimental structural studies and structure-based drug design. Here, we demonstrate that a Q151M substitution alone at the nucleotide-binding site (N-site) of human immunodeficiency virus type-1 (HIV-1) RT renders HIV-1 highly sensitive to entecavir (ETV), a potent nucleoside analogue RT inhibitor (NRTI) against HBV. The results suggest that Met151 forms a transient hydrophobic interaction with the cyclopentyl methylene of ETV, a characteristic hydrophobic moiety of ETV. We thus solved the crystal structures of HIV-1 RT:DNA complex with bound dGTP or ETV-triphosphate (ETV-TP). The structures revealed that ETV-TP is accommodated at the N-site slightly apart from the ribose ring of the 3'-end nucleotide, compared to the position of bound dGTP and previously reported NRTI/dNTP. In addition, the protruding methylene group of bound ETV-TP directly pushes the side-chain of Met184 backward. Met184 is a key residue that confers ETV resistance upon substitution with smaller Ile/Val. These results provide novel insights into NRTI binding to the N-site and further provide important clues for the development of novel anti-HBV/HIV-1 RT inhibitors to overcome critical drug resistance.

PubMed: 29374261
DOI: 10.1038/s41598-018-19602-9

Experimental method

X-RAY DIFFRACTION (2.381 Å)