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Developing Adnectins that target SRC co-activator binding to PXR: a structural approach toward understanding promiscuity of PXR.
- Source :
-
Journal of molecular biology [J Mol Biol] 2015 Feb 27; Vol. 427 (4), pp. 924-942. Date of Electronic Publication: 2015 Jan 08. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Binding Sites
Crystallography, X-Ray
Humans
Lignans metabolism
Models, Molecular
Molecular Sequence Data
Pregnane X Receptor
Protein Binding
Protein Structure, Tertiary
Receptors, CCR1 metabolism
Sequence Alignment
Surface Plasmon Resonance
Urea chemistry
Urea metabolism
Urea pharmacology
Valine chemistry
Valine metabolism
Valine pharmacology
Nuclear Receptor Coactivator 1 chemistry
Receptors, CCR1 antagonists & inhibitors
Receptors, Steroid chemistry
Urea analogs & derivatives
Valine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1089-8638
- Volume :
- 427
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 25579995
- Full Text :
- https://doi.org/10.1016/j.jmb.2014.12.022