2IC3

Crystal Structure of K103N/Y181C Mutant HIV-1 Reverse Transcriptase (RT) in Complex with Nonnucleoside Inhibitor HBY 097

2IC3 の概要

• エントリーDOI: 10.2210/pdb2ic3/pdb
• 関連するPDBエントリー: 1bqM 1DLO 1SV5 1UWB 2iaj
• 分子名称: Reverse transcriptase/ribonuclease H (p66 RT), Reverse transcriptase/ribonuclease H (p51 RT), MANGANESE (II) ION, ... (5 entities in total)
• 機能のキーワード: rt, nnrti, nonnucleoside inhibitor, drug resistance, hiv, aids, drug design, transferase
• 由来する生物種: Human immunodeficiency virus type 1 BH10; 詳細
• 細胞内の位置: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366 P03366
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 116791.82

構造登録者

Das, K.,Arnold, E. (登録日: 2006-09-12, 公開日: 2006-12-19, 最終更新日: 2023-08-30)

主引用文献

Das, K.,Sarafianos, S.G.,Clark, A.D.,Boyer, P.L.,Hughes, S.H.,Arnold, E.
Crystal Structures of Clinically Relevant Lys103Asn/Tyr181Cys Double Mutant HIV-1 Reverse Transcriptase in Complexes with ATP and Non-nucleoside Inhibitor HBY 097.
J.Mol.Biol., 365:77-89, 2007

PubMed Abstract: Lys103Asn and Tyr181Cys are the two mutations frequently observed in patients exposed to various non-nucleoside reverse transcriptase inhibitor drugs (NNRTIs). Human immunodeficiency virus (HIV) strains containing both reverse transcriptase (RT) mutations are resistant to all of the approved NNRTI drugs. We have determined crystal structures of Lys103Asn/Tyr181Cys mutant HIV-1 RT with and without a bound non-nucleoside inhibitor (HBY 097, (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione) at 3.0 A and 2.5 A resolution, respectively. The structure of the double mutant RT/HBY 097 complex shows a rearrangement of the isopropoxycarbonyl group of HBY 097 compared to its binding with wild-type RT. HBY 097 makes a hydrogen bond with the thiol group of Cys181 that helps the drug retain potency against the Tyr181Cys mutation. The structure of the unliganded double mutant HIV-1 RT showed that Lys103Asn mutation facilitates coordination of a sodium ion with Lys101 O, Asn103 N and O(delta1), Tyr188 O(eta), and two water molecules. The formation of the binding pocket requires the removal of the sodium ion. Although the RT alone and the RT/HBY 097 complex were crystallized in the presence of ATP, only the RT has an ATP coordinated with two Mn(2+) at the polymerase active site. The metal coordination mimics a reaction intermediate state in which complete octahedral coordination was observed for both metal ions. Asp186 coordinates at an axial position whereas the carboxylates of Asp110 and Asp185 are in the planes of coordination of both metal ions. The structures provide evidence that NNRTIs restrict the flexibility of the YMDD loop and prevent the catalytic aspartate residues from adopting their metal-binding conformations.

PubMed: 17056061
DOI: 10.1016/j.jmb.2006.08.097

実験手法

X-RAY DIFFRACTION (3 Å)