气候变化领域集成服务门户(CCPortal): Structural basis of second-generation HIV integrase inhibitor action and viral resistance

CCPortal

DOI	10.1126/science.aay4919
	Structural basis of second-generation HIV integrase inhibitor action and viral resistance
	Cook N.J.; Li W.; Berta D.; Badaoui M.; Ballandras-Colas A.; Nans A.; Kotecha A.; Rosta E.; Engelman A.N.; Cherepanov P.
发表日期	2020
ISSN	0036-8075
起始页码	806
结束页码	810
卷号	367 期号:6479
英文摘要	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. © 2020 American Association for the Advancement of Science. All rights reserved.
关键词	bictegravir dolutegravir lens epithelium derived growth factor magnesium ion bictegravir dolutegravir fused heterocyclic rings glutamine glycine histidine integrase integrase inhibitor magnesium serine acquired immune deficiency syndrome amino acid drug human immunodeficiency virus inhibitor protein ultrastructure virus amino acid substitution amino terminal sequence Article carboxy terminal sequence cryoelectron microscopy DNA binding drug design drug protein binding drug structure enzyme active site gene mutation Human immunodeficiency virus 1 in vitro study molecular dynamics molecular stability nonhuman pharmacophore polarization priority journal protonation virus resistance antiviral resistance chemistry genetics human mutation procedures single molecule imaging Amino Acid Substitution Catalytic Domain Cryoelectron Microscopy Drug Resistance, Viral Glutamine Glycine Heterocyclic Compounds, 3-Ring Heterocyclic Compounds, 4 or More Rings Histidine HIV Integrase HIV Integrase Inhibitors Humans Magnesium Mutation Serine Single Molecule Imaging
语种	英语
来源机构	Science
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/133730
推荐引用方式 GB/T 7714	Cook N.J.,Li W.,Berta D.,et al. Structural basis of second-generation HIV integrase inhibitor action and viral resistance[J]. Science,2020,367(6479).
APA	Cook N.J..,Li W..,Berta D..,Badaoui M..,Ballandras-Colas A..,...&Cherepanov P..(2020).Structural basis of second-generation HIV integrase inhibitor action and viral resistance.,367(6479).
MLA	Cook N.J.,et al."Structural basis of second-generation HIV integrase inhibitor action and viral resistance".367.6479(2020).