8d3s

HIV-1 Integrase Catalytic Core Domain F185H Mutant Complexed with BKC-110HIV-1 Integrase Catalytic Core Domain F185H Mutant Complexed with BKC-110

Structural highlights 8d3s is a 1 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.84Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1((Y99H/A128T IN)) variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. While both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCD(Y99H/A128T) + PIR complex. Consequently, full-length IN(Y99H/A128T) was substantially less susceptible to the PIR induced hyper-multimerization than the WT protein, and HIV-1((Y99H/A128T IN)) conferred >150-fold resistance to the inhibitor compared to the WT virus. By rationally modifying PIR we have developed its analog EKC110, which readily induced hyper-multimerization of IN(Y99H/A128T) in vitro and was ~14-fold more potent against HIV-1((Y99H/A128T IN)) than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use. The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.,Dinh T, Tber Z, Rey JS, Mengshetti S, Annamalai AS, Haney R, Briganti L, Amblard F, Fuchs JR, Cherepanov P, Kim K, Schinazi RF, Perilla JR, Kim B, Kvaratskhelia M bioRxiv [Preprint]. 2024 Jan 26:2024.01.26.577387. doi: , 10.1101/2024.01.26.577387. PMID:38328097 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Retroviral integrase 3D structures

spinqualitylabelsall models 8d3s, resolution 1.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image