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TitleStructural basis of second-generation HIV integrase inhibitor action and viral resistance.
Journal, issue, pagesScience, Vol. 367, Issue 6479, Page 806-810, Year 2020
Publish dateFeb 14, 2020
AuthorsNicola J Cook / Wen Li / Dénes Berta / Magd Badaoui / Allison Ballandras-Colas / Andrea Nans / Abhay Kotecha / Edina Rosta / Alan N Engelman / Peter Cherepanov /
PubMed AbstractAlthough 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.
External linksScience / PubMed:32001525 / PubMed Central
MethodsEM (single particle)
Resolution2.81 - 3.36 Å
Structure data

EMDB-10041, PDB-6rwl:
SIVrcm intasome
Method: EM (single particle) / Resolution: 3.36 Å

EMDB-10042, PDB-6rwm:
SIVrcm intasome in complex with bictegravir
Method: EM (single particle) / Resolution: 2.81 Å

EMDB-10043, PDB-6rwn:
SIVrcm intasome in complex with dolutegravir
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-10044, PDB-6rwo:
SIVrcm intasome (Q148H/G140S) in complex with bictegravir
Method: EM (single particle) / Resolution: 3.05 Å

Chemicals

ChemComp-ZN:
ZINC ION / Zinc

ChemComp-MG:
MAGNESIUM ION / Magnesium

ChemComp-KLQ:
Bictegravir / antivirus, inhibitor*YM / Bictegravir

ChemComp-CL:
CHLORIDE ION / Chloride

ChemComp-HOH:
WATER / Water

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 / medication, antiretroviral*YM / Dolutegravir

Source
  • simian immunodeficiency virus
KeywordsAmino Acid Substitution / Catalytic Domain / Cryoelectron Microscopy / Drug Resistance, Viral / Glutamine / Glycine / HIV Integrase / HIV Integrase Inhibitors / Heterocyclic Compounds, 3-Ring / Heterocyclic Compounds, 4 or More Rings / Histidine / Humans / Magnesium / Mutation / Oxazines / Piperazines / Pyridones / Serine / Single Molecule Imaging / bictegravir / dolutegravir / RECOMBINATION / retroviral integrase / lentivirus / strand transfer inhibior / protein-DNA complex

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