In Silico Adoption of an Orphan Nuclear Receptor NR4A1.
A 4.1 μs molecular dynamics simulation of the NR4A1 (hNur77) apo-protein has been undertaken and a previously undetected druggable pocket has become apparent that is located remotely from the 'traditional' nuclear receptor ligand-binding site. A NR4A1/bis-indole ligand complex at this novel site has been found to be stable over 1 μs of simulation and to result in an interesting conformational transmission to a remote loop that has the capacity to communicate with a NBRE within a RXR-α/NR4A1 heterodimer. Several features of the simulations undertaken indicate how NR4A1 can be affected by alternate-site modulators.
Computer-Chemie-Centrum der Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstraße 25, 91052, Erlangen, Germany.
Harald
H
Lanig
ETH Zürich, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Straße 10, 8093, Zürich, Switzerland.
Felix
F
Reisen
Centre for Molecular Design, School of Pharmacy and Biomolecular Sciences, University of Portsmouth, King Henry Building, Portsmouth, PO1 2DY, United Kingdom.
David
D
Whitley
ETH Zürich, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Straße 10, 8093, Zürich, Switzerland.
Gisbert
G
Schneider
School of Pharmacy and Biomolecular Sciences, University of Portsmouth, St. Michael's Building, White Swan Road, Portsmouth, PO1 2DT, United Kingdom.
Lee
L
Banting
Computer-Chemie-Centrum der Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstraße 25, 91052, Erlangen, Germany; Centre for Molecular Design, School of Pharmacy and Biomolecular Sciences, University of Portsmouth, King Henry Building, Portsmouth, PO1 2DY, United Kingdom.
Timothy
T
Clark
D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D047490:Retinoid X Receptor alpha / Q000378:metabolism*
D008024:Ligands; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047490:Retinoid X Receptor alpha