6rwn

SIVrcm intasome in complex with dolutegravir

Loading... Status: waiting for Mol* initialization Structural highlights 6rwn is a 16 chain structure with sequence from Simian immunodeficiency virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.1Å Ligands: CL, DLU, MG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function E1ANT8_SIV Publication Abstract from PubMed 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. Structural basis of second-generation HIV integrase inhibitor action and viral resistance.,Cook NJ, Li W, Berta D, Badaoui M, Ballandras-Colas A, Nans A, Kotecha A, Rosta E, Engelman AN, Cherepanov P Science. 2020 Feb 14;367(6479):806-810. doi: 10.1126/science.aay4919. Epub 2020, Jan 30. PMID:32001525 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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