4S0T

STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND WITH ADNECTIN-1 AND COMPOUND-1

Summary for 4S0T

• Entry DOI: 10.2210/pdb4s0t/pdb
• Related: 4S0S 4XHD
• Descriptor: Nuclear receptor subfamily 1 group I member 2, Adnectin-1, N-{(2R)-1-[(4S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl]-3-methyl-1-oxobutan-2-yl}-2-cyclopropylacetamide (3 entities in total)
• Functional Keywords: nuclear receptor, multiple binding modes, xenobiotic, promiscuous, nuclear hormone receptor, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : O75469
• Total number of polymer chains: 4
• Total formula weight: 99754.76

Authors

Khan, J.A.,Camac, D.M. (deposition date: 2015-01-05, release date: 2015-02-04, Last modification date: 2024-02-28)

Primary citation

Khan, J.A.,Camac, D.M.,Low, S.,Tebben, A.J.,Wensel, D.L.,Wright, M.C.,Su, J.,Jenny, V.,Gupta, R.D.,Ruzanov, M.,Russo, K.A.,Bell, A.,An, Y.,Bryson, J.W.,Gao, M.,Gambhire, P.,Baldwin, E.T.,Gardner, D.,Cavallaro, C.L.,Duncia, J.V.,Hynes, J.
Developing Adnectins That Target SRC Co-Activator Binding to PXR: A Structural Approach toward Understanding Promiscuity of PXR.
J.Mol.Biol., 427:924-942, 2015

PubMed Abstract: The 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 ((10)Fn3), 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.

PubMed: 25579995
DOI: 10.1016/j.jmb.2014.12.022

Experimental method

X-RAY DIFFRACTION (3.14 Å)