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6KDK

HIV-1 reverse transcriptase with Q151M/Y115F/F116Y:DNA:dCTP ternary complex

Summary for 6KDK
Entry DOI10.2210/pdb6kdk/pdb
Related PRD IDPRD_900003
DescriptorHIV-1 reverse transcriptase p66 subunit, HIV-1 RT p51 subunit, DNA/RNA (38-MER), ... (8 entities in total)
Functional Keywordsdctp, hiv-1, hbv, reverse transcriptase, drug resistance, drug sensitivity, transferase-dna complex, replication, transferase/dna
Biological sourceHuman immunodeficiency virus 1
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Total number of polymer chains6
Total formula weight257012.51
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 citationYasutake, 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: 32080249
DOI: 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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