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TitleStructural basis of second-generation HIV integrase inhibitor action and viral resistance.
Journal, issue, pagesScience, Year 2020
Publish dateJan 30, 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 AbstractDespite worldwide prescription, the mechanistic basis for superiority of second-generation HIV integrase (IN) strand transfer inhibitors (INSTIs) is poorly understood. We use single-particle cryo- ...Despite worldwide prescription, the mechanistic basis for superiority of second-generation HIV integrase (IN) strand transfer inhibitors (INSTIs) is poorly understood. We use single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near atomic resolution. Q148H/G140S amino acid substitutions in IN that pervade 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, which are critical for antagonizing Q148H/G140S mutant virus. 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 important class of anti-HIV/AIDS therapeutics.
External linksPubMed:32001525 / Publisher's page
KeywordsRECOMBINATION / retroviral integrase / lentivirus / strand transfer inhibior / protein-DNA complex
MethodsEM (single particle)
Resolution2.81 - 3.36 A
Structure data

EMDB-10041:
SIVrcm intasome

EMDB-10042:
SIVrcm intasome in complex with bictegravir

EMDB-10043:
SIVrcm intasome in complex with dolutegravir

EMDB-10044:
SIVrcm intasome (Q148/G140S) in complex with bictegravir

PDB-6rwl:
SIVrcm intasome

PDB-6rwm:
SIVrcm intasome in complex with bictegravir

PDB-6rwn:
SIVrcm intasome in complex with dolutegravir

PDB-6rwo:
SIVrcm intasome (Q148/G140S) in complex with bictegravir

Chemicals

ChemComp-ZN:
ZINC ION / Zinc

ChemComp-MG:
MAGNESIUM ION / Magnesium

ChemComp-KLQ:
Bictegravir / 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

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