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Developing Adnectins That Target SRC Co-Activator Binding to PXR: A Structural Approach toward Understanding Promiscuity of PXR

2015; Elsevier BV; Volume: 427; Issue: 4 Linguagem: Inglês

10.1016/j.jmb.2014.12.022

1089-8638

Javed Khan, Daniel M. Camac, Simon Low, Andrew J. Tebben, David Wensel, Martin C. Wright, Julie Su, Victoria Jenny, Ruchira Das Gupta, Max Ruzanov, Katie Russo, Aneka Bell, Yongmi An, James W. Bryson, Mian Gao, Pallavi Gambhire, Eric T. Baldwin, Daniel S. Gardner, Cullen L. Cavallaro, John V. Duncia, John Hynes,

Ubiquitin and proteasome pathways

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 (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.