|Title||Structural basis of second-generation HIV integrase inhibitor action and viral resistance.|
|Journal, issue, pages||Science, Year 2020|
|Publish date||Jan 30, 2020|
|Authors||Nicola J Cook / Wen Li / Dénes Berta / Magd Badaoui / Allison Ballandras-Colas / Andrea Nans / Abhay Kotecha / Edina Rosta / Alan N Engelman / Peter Cherepanov /|
|PubMed Abstract||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- ...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 links||PubMed:32001525 / Publisher's page|
|Keywords||RECOMBINATION / retroviral integrase / lentivirus / strand transfer inhibior / protein-DNA complex|
|Methods||EM (single particle)|
|Resolution||2.81 - 3.36 A|
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