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キーワード
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

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Structure paper

タイトル	Structural basis of second-generation HIV integrase inhibitor action and viral resistance.
ジャーナル・号・ページ	Science, Vol. 367, Issue 6479, Page 806-810, Year 2020
掲載日	2020年2月14日
著者	Nicola J Cook / Wen Li / Dénes Berta / Magd Badaoui / Allison Ballandras-Colas / Andrea Nans / Abhay Kotecha / Edina Rosta / Alan N Engelman / Peter Cherepanov /
PubMed 要旨	Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We ...Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.
リンク	Science / PubMed:32001525 / PubMed Central
手法	EM (単粒子)
解像度	2.81 - 3.36 Å
構造データ	10041 6rwl EMDB-10041, PDB-6rwl: SIVrcm intasome 手法: EM (単粒子) / 解像度: 3.36 Å 10042 6rwm EMDB-10042, PDB-6rwm: SIVrcm intasome in complex with bictegravir 手法: EM (単粒子) / 解像度: 2.81 Å 10043 6rwn EMDB-10043, PDB-6rwn: SIVrcm intasome in complex with dolutegravir 手法: EM (単粒子) / 解像度: 3.1 Å 10044 6rwo EMDB-10044, PDB-6rwo: SIVrcm intasome (Q148H/G140S) in complex with bictegravir 手法: EM (単粒子) / 解像度: 3.05 Å
化合物	ChemComp-ZN: Unknown entry ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-KLQ: Bictegravir / 阻害剤YM / Bictegravir ChemComp-CL: Unknown entry / クロリド / 塩化物 ChemComp-HOH: WATER / 水 ChemComp-DLU: (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide / ドルテグラビル / 薬剤, 抗レトロウイルス剤YM / ドルテグラビル
由来	simian immunodeficiency virus (サル免疫不全ウイルス)
キーワード	RECOMBINATION (遺伝的組換え) / retroviral integrase (インテグラーゼ) / lentivirus (レンチウイルス属) / strand transfer inhibior / protein-DNA complex (デオキシリボ核酸)