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STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN WITH COMPOUND-1STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN WITH COMPOUND-1
Structural highlights
Function[NR1I2_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 PubMedThe human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated "Adnectins", derived from 10th fibronectin type III domain (10Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and CCR1 (CC chemokine receptor-1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in not only targeting the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest. Developing Adnectins That Target SRC Co-Activator Binding to PXR: A Structural Approach toward Understanding Promiscuity of PXR.,Khan JA, Camac DM, Low S, Tebben AJ, Wensel DL, Wright MC, Su J, Jenny V, Gupta RD, Ruzanov M, Russo KA, Bell A, An Y, Bryson JW, Gao M, Gambhire P, Baldwin ET, Gardner D, Cavallaro CL, Duncia JV, Hynes J Jr J Mol Biol. 2015 Jan 8. pii: S0022-2836(15)00002-9. doi:, 10.1016/j.jmb.2014.12.022. PMID:25579995[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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