6RWM

SIVrcm intasome in complex with bictegravir

Summary for 6RWM

• Entry DOI: 10.2210/pdb6rwm/pdb
• EMDB information: 10042
• Descriptor: Pol protein, DNA (5'-D(P*GP*CP*TP*AP*AP*GP*AP*AP*AP*AP*AP*TP*CP*TP*CP*TP*AP*CP*CP*A)-3'), DNA (5'-D(*AP*AP*CP*TP*GP*GP*TP*AP*GP*AP*GP*AP*TP*TP*TP*TP*TP*CP*TP*TP*AP*GP*C)-3'), ... (8 entities in total)
• Functional Keywords: retroviral integrase, lentivirus, strand transfer inhibior, protein-dna complex, recombination
• Biological source: Simian immunodeficiency virus; More
• Total number of polymer chains: 16
• Total formula weight: 433093.41

Authors

Cherepanov, P.,Nans, A.,Cook, N. (deposition date: 2019-06-05, release date: 2020-02-05, Last modification date: 2024-07-10)

Primary citation

Cook, N.J.,Li, W.,Berta, D.,Badaoui, M.,Ballandras-Colas, A.,Nans, A.,Kotecha, A.,Rosta, E.,Engelman, A.N.,Cherepanov, P.
Structural basis of second-generation HIV integrase inhibitor action and viral resistance.
Science, 367:806-810, 2020

PubMed Abstract: 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.

PubMed: 32001525
DOI: 10.1126/science.aay4919

Experimental method

ELECTRON MICROSCOPY (2.81 Å)