Abstract
A 4.1μs 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.
Highlights
Protein-ligand interactions and protein dynamics “Orphan” nuclear receptors exhibit no obvious ligand-binding pocket in their X-ray crystal structures; many of their biological functions are poorly understood
A hydrophobic co-regulator cleft comprised of helices 3, 5 and 12 is found in many members of the family. It plays a vital role in recruiting co-activators and co-repressors during gene transcription and its access is normally modulated by helix 12 within the non-orphan nuclear receptors (NRs), which undergo a conformational change on ligand binding
Different small molecule modulators of NR4A1 and Nurr1 are known, [33] their mode of binding and mechanism of action remain unknown. These observations suggest that NR4A1 exhibits druggable binding regions for which effective modulators can be developed analogously to those for the ERR receptors, which were originally thought not to have accessible ligand-binding domains
Summary
Data Availability Statement: Structural data (PDB files) are included in the Supporting Information. A 4.1μs 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/bisindole 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
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