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Structure paper

タイトル	Structural basis for strand-transfer inhibitor binding to HIV intasomes.
ジャーナル・号・ページ	Science, Vol. 367, Issue 6479, Page 810-814, Year 2020
掲載日	2020年2月14日
著者	Dario Oliveira Passos / Min Li / Ilona K Jóźwik / Xue Zhi Zhao / Diogo Santos-Martins / Renbin Yang / Steven J Smith / Youngmin Jeon / Stefano Forli / Stephen H Hughes / Terrence R Burke / Robert Craigie / Dmitry Lyumkis /
PubMed 要旨	The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of ...The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretroviral drugs, integrase strand-transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target. Here, we present high-resolution cryo-electron microscopy structures of HIV intasomes bound to the latest generation of INSTIs. These structures highlight how small changes in the integrase active site can have notable implications for drug binding and design and provide mechanistic insights into why a leading INSTI retains efficacy against a broad spectrum of drug-resistant variants. The data have implications for expanding effective treatments available for HIV-infected individuals.
リンク	Science / PubMed:32001521 / PubMed Central
手法	EM (単粒子)
解像度	2.8 - 3.4 Å
構造データ	20481 6put EMDB-20481, PDB-6put: Structure of HIV cleaved synaptic complex (CSC) intasome bound with calcium 手法: EM (単粒子) / 解像度: 2.9 Å 20483 6puw EMDB-20483, PDB-6puw: Structure of HIV cleaved synaptic complex (CSC) intasome bound with magnesium and Bictegravir (BIC) 手法: EM (単粒子) / 解像度: 2.9 Å 20484 6puy EMDB-20484, PDB-6puy: Structure of HIV cleaved synaptic complex (CSC) intasome bound with magnesium and INSTI XZ426 (compound 4d) 手法: EM (単粒子) / 解像度: 2.8 Å 20485 6puz EMDB-20485, PDB-6puz: Structure of HIV cleaved synaptic complex (CSC) intasome bound with magnesium and INSTI XZ446 (compound 4f) 手法: EM (単粒子) / 解像度: 2.8 Å 21038 6v3k EMDB-21038, PDB-6v3k: Structure of HIV cleaved synaptic complex (CSC) intasome bound with magnesium and INSTI XZ419 (compound 4c) 手法: EM (単粒子) / 解像度: 3.4 Å
化合物	ChemComp-CA: Unknown entry / カルシウムジカチオン ChemComp-ZN: Unknown entry ChemComp-HOH: WATER / 水 ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-KLQ: Bictegravir / 阻害剤YM / Bictegravir ChemComp-OZ1: 4-amino-N-[(2,4-difluorophenyl)methyl]-1-hydroxy-6-(6-hydroxyhexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ChemComp-XXJ: 4-azanyl-N-[[2,4-bis(fluoranyl)phenyl]methyl]-1-oxidanyl-2-oxidanylidene-6-[2-(phenylsulfonyl)ethyl]-1,8-naphthyridine-3-carboxamide ChemComp-QUW*: 4-azanyl-N-[[2,4-bis(fluoranyl)phenyl]methyl]-1-oxidanyl-2-oxidanylidene-6-(5-oxidanylpentyl)-1,8-naphthyridine-3-carboxamide
由来	human immunodeficiency virus 1 (ヒト免疫不全ウイルス) hiv (ヒト免疫不全ウイルス) saccharolobus solfataricus (strain atcc 35092 / dsm 1617 / jcm 11322 / p2) (古細菌)
キーワード	VIRAL PROTEIN/DNA (ウイルス性) / integrase (インテグラーゼ) / intasome / enzyme (酵素) / transposition / VIRAL PROTEIN (ウイルスタンパク質) / VIRAL PROTEIN-DNA complex (ウイルス性)