5TXL

STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE (RT) TERNARY COMPLEX WITH A DOUBLE STRANDED DNA AND AN INCOMING DATP

5TXL の概要

• エントリーDOI: 10.2210/pdb5txl/pdb
• 関連するPDBエントリー: 3JSM 3JYT 3KLE 3V4I 4PQU 5TXM 5TXN 5TXO 5TXP
• 関連するBIRD辞書のPRD_ID: PRD_900003
• 分子名称: HIV-1 REVERSE TRANSCRIPTASE P66 SUBUNIT, HIV-1 REVERSE TRANSCRIPTASE P51 SUBUNIT, DNA (5'-D(*AP*TP*GP*GP*AP*AP*GP*GP*CP*GP*CP*CP*CP*GP*AP*AP*CP*AP*GP*GP*GP*AP* CP*TP*GP*TP*G)-3'), ... (10 entities in total)
• 機能のキーワード: rt, dna, crosslink, n site complex, pyrophosphorolysis, p51, p66, transferase, drug resistance, mutation, transferase-dna complex, transferase/dna
• 由来する生物種: Human immunodeficiency virus type 1 group M subtype B (isolate BH10) (HIV-1); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 263819.97

構造登録者

Das, K.,Martinez, S.M.,Arnold, E. (登録日: 2016-11-17, 公開日: 2017-04-05, 最終更新日: 2024-10-23)

主引用文献

Das, K.,Martinez, S.E.,Arnold, E.
Structural Insights into HIV Reverse Transcriptase Mutations Q151M and Q151M Complex That Confer Multinucleoside Drug Resistance.
Antimicrob. Agents Chemother., 61:-, 2017

PubMed Abstract: HIV-1 reverse transcriptase (RT) is targeted by multiple drugs. RT mutations that confer resistance to nucleoside RT inhibitors (NRTIs) emerge during clinical use. Q151M and four associated mutations, A62V, V75I, F77L, and F116Y, were detected in patients failing therapies with dideoxynucleosides (didanosine [ddI], zalcitabine [ddC]) and/or zidovudine (AZT). The cluster of the five mutations is referred to as the Q151M complex (Q151Mc), and an RT or virus containing Q151Mc exhibits resistance to multiple NRTIs. To understand the structural basis for Q151M and Q151Mc resistance, we systematically determined the crystal structures of the wild-type RT/double-stranded DNA (dsDNA)/dATP (complex I), wild-type RT/dsDNA/ddATP (complex II), Q151M RT/dsDNA/dATP (complex III), Q151Mc RT/dsDNA/dATP (complex IV), and Q151Mc RT/dsDNA/ddATP (complex V) ternary complexes. The structures revealed that the deoxyribose rings of dATP and ddATP have 3'-endo and 3'-exo conformations, respectively. The single mutation Q151M introduces conformational perturbation at the deoxynucleoside triphosphate (dNTP)-binding pocket, and the mutated pocket may exist in multiple conformations. The compensatory set of mutations in Q151Mc, particularly F116Y, restricts the side chain flexibility of M151 and helps restore the DNA polymerization efficiency of the enzyme. The altered dNTP-binding pocket in Q151Mc RT has the Q151-R72 hydrogen bond removed and has a switched conformation for the key conserved residue R72 compared to that in wild-type RT. On the basis of a modeled structure of hepatitis B virus (HBV) polymerase, the residues R72, Y116, M151, and M184 in Q151Mc HIV-1 RT are conserved in wild-type HBV polymerase as residues R41, Y89, M171, and M204, respectively; functionally, both Q151Mc HIV-1 and wild-type HBV are resistant to dideoxynucleoside analogs.

PubMed: 28396546
DOI: 10.1128/AAC.00224-17

実験手法

X-RAY DIFFRACTION (2.501 Å)