6hj2
From Proteopedia
Crystal structure of hPXR in complex with dabrafenib
Structural highlights
FunctionNR1I2_HUMAN Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedDabrafenib is an anticancer drug currently used in the clinics, alone or in combination. However, dabrafenib was recently shown to potently activate the human nuclear receptor pregnane X receptor (PXR). PXR activation increases the clearance of various chemicals and drugs, including dabrafenib itself. It may also enhance cell proliferation and tumor aggressiveness. Therefore, there is a need for rational design of a potent protein kinase B-Raf inhibitor devoid of binding to the secondary target PXR and resisting rapid metabolism. By determining the crystal structure of dabrafenib bound to PXR and analyzing its mode of binding to both PXR and its primary target, B-Raf-V600E, we were able to derive new compounds with nanomolar activity against B-Raf and no detectable affinity for PXR. The crystal structure of B-Raf in complex with our lead compound revealed a subdomain swapping of the activation loop with potentially important functional implications for a prolonged inhibition of B-Raf-V600E. Structure-Based and Knowledge-Informed Design of B-Raf Inhibitors Devoid of Deleterious PXR Binding.,Schneider M, Delfosse V, Gelin M, Grimaldi M, Granell M, Heriaud L, Pons JL, Cohen Gonsaud M, Balaguer P, Bourguet W, Labesse G J Med Chem. 2022 Jan 27;65(2):1552-1566. doi: 10.1021/acs.jmedchem.1c01354. Epub , 2021 Dec 27. PMID:34958586[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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