8X1Z

HIV-1 reverse transcriptase mutant Q151M/Y115F/F116Y:DNA:E-CFCP-TP ternary complex

Summary for 8X1Z

• Entry DOI: 10.2210/pdb8x1z/pdb
• Descriptor: HIV-1 reverse transcriptase p66 subunit, HIV-1 RT p51 subunit, DNA/RNA (38-MER), ... (7 entities in total)
• Functional Keywords: reverse transcriptase, hiv-1, hbv, drug resistance, nucleoside analogue, e-cfcp, transferase
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 6
• Total formula weight: 256868.39

Authors

Yasutake, Y.,Hattori, S.I.,Mitsuya, H. (deposition date: 2023-11-09, release date: 2024-07-17)

Primary citation

Yasutake, Y.,Hattori, S.I.,Kumamoto, H.,Tamura, N.,Maeda, K.,Mitsuya, H.
Deviated binding of anti-HBV nucleoside analog E-CFCP-TP to the reverse transcriptase active site attenuates the effect of drug-resistant mutations.
Sci Rep, 14:15742-15742, 2024

PubMed Abstract: While certain human hepatitis B virus-targeting nucleoside analogs (NAs) serve as crucial anti-HBV drugs, HBV yet remains to be a major global health threat. E-CFCP is a 4'-modified and fluoromethylenated NA that exhibits potent antiviral activity against both wild-type and drug-resistant HBVs but less potent against human immunodeficiency virus type-1 (HIV-1). Here, we show that HIV-1 with HBV-associated amino acid substitutions introduced into the RT's dNTP-binding site (N-site) is highly susceptible to E-CFCP. We determined the X-ray structures of HBV-associated HIV-1 RT mutants complexed with DNA:E-CFCP-triphosphate (E-CFCP-TP). The structures revealed that exocyclic fluoromethylene pushes the Met184 sidechain backward, and the resultant enlarged hydrophobic pocket accommodates both the fluoromethylene and 4'-cyano moiety of E-CFCP. Structural comparison with the DNA:dGTP/entecavir-triphosphate complex also indicated that the cyclopentene moiety of the bound E-CFCP-TP is slightly skewed and deviated. This positioning partly corresponds to that of the bound dNTP observed in the HIV-1 RT mutant with drug-resistant mutations F160M/M184V, resulting in the attenuation of the structural effects of F160M/M184V substitutions. These results expand our knowledge of the interactions between NAs and the RT N-site and should help further design antiviral NAs against both HIV-1 and HBV.

PubMed: 38977798
DOI: 10.1038/s41598-024-66505-z

Experimental method

X-RAY DIFFRACTION (2.62 Å)