6KDK
HIV-1 reverse transcriptase with Q151M/Y115F/F116Y:DNA:dCTP ternary complex
Summary for 6KDK
Entry DOI | 10.2210/pdb6kdk/pdb |
Related PRD ID | PRD_900003 |
Descriptor | HIV-1 reverse transcriptase p66 subunit, HIV-1 RT p51 subunit, DNA/RNA (38-MER), ... (8 entities in total) |
Functional Keywords | dctp, hiv-1, hbv, reverse transcriptase, drug resistance, drug sensitivity, transferase-dna complex, replication, transferase/dna |
Biological source | Human immunodeficiency virus 1 More |
Total number of polymer chains | 6 |
Total formula weight | 257012.51 |
Authors | Yasutake, Y.,Hattori, S.I.,Tamura, N.,Maeda, K. (deposition date: 2019-07-02, release date: 2020-03-04, Last modification date: 2023-11-22) |
Primary citation | Yasutake, Y.,Hattori, S.I.,Tamura, N.,Matsuda, K.,Kohgo, S.,Maeda, K.,Mitsuya, H. Structural features in common of HBV and HIV-1 resistance against chirally-distinct nucleoside analogues entecavir and lamivudine. Sci Rep, 10:3021-3021, 2020 Cited by PubMed Abstract: Chronic hepatitis B virus (HBV) infection is a major public health problem that affects millions of people worldwide. Nucleoside analogue reverse transcriptase (RT) inhibitors, such as entecavir (ETV) and lamivudine (3TC), serve as crucial anti-HBV drugs. However, structural studies of HBV RT have been hampered due to its unexpectedly poor solubility. Here, we show that human immunodeficiency virus type-1 (HIV-1) with HBV-associated amino acid substitutions Y115F/F116Y/Q151M in its RT (HIV) is highly susceptible to ETV and 3TC. Additionally, we experimentally simulated previously reported ETV/3TC resistance for HBV using HIV with F160M/M184V (L180M/M204V in HBV RT) substituted. We determined crystal structures for HIV-1 RT:DNA complexed with 3TC-triphosphate (3TC-TP)/ETV-triphosphate (ETV-TP)/dCTP/dGTP. These structures revealed an atypically tight binding conformation of 3TC-TP, where the Met184 side-chain is pushed away by the oxathiolane of 3TC-TP and exocyclic methylene of ETV-TP. Structural analysis of RT:DNA:3TC-TP also demonstrated that the loosely bound 3TC-TP is misaligned at the active site to prevent a steric clash with the side chain γ-methyl of Val184. These findings shed light on the common structural mechanism of HBV and HIV-1 resistance to 3TC and ETV and should aid in the design of new agents to overcome drug resistance to 3TC and ETV. PubMed: 32080249DOI: 10.1038/s41598-020-59775-w PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.56 Å) |
Structure validation
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