Crystal structures of the nuclear receptor, liver receptor homolog 1, bound to synthetic agonists
Crystal structures of the nuclear receptor, liver receptor homolog 1, bound to synthetic agonists
Liver receptor homolog 1 (NR5A2, LRH-1) is an orphan nuclear hormone receptor that regulates diverse biological processes, including metabolism, proliferation, and the resolution of endoplasmic reticulum stress. While preclinical and cellular studies demonstrate that LRH-1 has great potential as a therapeutic target for metabolic diseases and cancer, development of LRH-1 modulators has been difficult. Recently, systematic modifications to one of the few known chemical scaffolds capable of activating LRH-1 failed to improve efficacy substantially. Moreover, mechanisms through which LRH-1 is activated by synthetic ligands are entirely unknown. Here, we use x-ray crystallography and other structural methods to explore conformational changes and receptor-ligand interactions associated with LRH-1 activation by a set of related agonists. Unlike phospholipid (PL) LRH-1 ligands, these agonists bind deep in the pocket and do not interact with residues near the mouth, nor do they expand the pocket like PLs. Unexpectedly, two closely related agonists with similar efficacies (GSK8470 and RJW100) exhibit completely different binding modes. The dramatic repositioning is influenced by a differential ability to establish stable, face-to-face ?-?-stacking with LRH-1 residue H390, as well as by a novel polar interaction mediated by the RJW100 hydroxyl group. The differing binding modes result in distinct mechanisms of action for the two agonists. Finally, we identify a network of conserved water molecules near the ligand-binding site that are important for activation by both agonists. This work reveals a previously unappreciated complexity associated with LRH-1 agonist development and offers insights into rational design strategies.
25281-25291
Mays, Suzanne G.
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Okafor, C. Denise
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Whitby, Richard
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Goswami, Devrishi
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Stec, Jozef
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Flynn, Autumn R.
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Dugan, Michael C.
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Jui, Nathan T.
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Griffin, Patrick R.
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Ortlund, Eric A.
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2 December 2016
Mays, Suzanne G.
4b7df6c0-7248-45d1-91ca-2484d9d3875e
Okafor, C. Denise
45ef9344-3774-4376-b424-3531f4626404
Whitby, Richard
45632236-ab00-4ad0-a02d-6209043e818b
Goswami, Devrishi
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Stec, Jozef
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Flynn, Autumn R.
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Dugan, Michael C.
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Jui, Nathan T.
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Griffin, Patrick R.
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Ortlund, Eric A.
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Mays, Suzanne G., Okafor, C. Denise, Whitby, Richard, Goswami, Devrishi, Stec, Jozef, Flynn, Autumn R., Dugan, Michael C., Jui, Nathan T., Griffin, Patrick R. and Ortlund, Eric A.
(2016)
Crystal structures of the nuclear receptor, liver receptor homolog 1, bound to synthetic agonists.
The Journal of Biological Chemistry, 291 (49), .
(doi:10.1074/jbc.M116.753541).
Abstract
Liver receptor homolog 1 (NR5A2, LRH-1) is an orphan nuclear hormone receptor that regulates diverse biological processes, including metabolism, proliferation, and the resolution of endoplasmic reticulum stress. While preclinical and cellular studies demonstrate that LRH-1 has great potential as a therapeutic target for metabolic diseases and cancer, development of LRH-1 modulators has been difficult. Recently, systematic modifications to one of the few known chemical scaffolds capable of activating LRH-1 failed to improve efficacy substantially. Moreover, mechanisms through which LRH-1 is activated by synthetic ligands are entirely unknown. Here, we use x-ray crystallography and other structural methods to explore conformational changes and receptor-ligand interactions associated with LRH-1 activation by a set of related agonists. Unlike phospholipid (PL) LRH-1 ligands, these agonists bind deep in the pocket and do not interact with residues near the mouth, nor do they expand the pocket like PLs. Unexpectedly, two closely related agonists with similar efficacies (GSK8470 and RJW100) exhibit completely different binding modes. The dramatic repositioning is influenced by a differential ability to establish stable, face-to-face ?-?-stacking with LRH-1 residue H390, as well as by a novel polar interaction mediated by the RJW100 hydroxyl group. The differing binding modes result in distinct mechanisms of action for the two agonists. Finally, we identify a network of conserved water molecules near the ligand-binding site that are important for activation by both agonists. This work reveals a previously unappreciated complexity associated with LRH-1 agonist development and offers insights into rational design strategies.
Text
JBC-2016-753541v2-Ortlund.pdf
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More information
Accepted/In Press date: 30 September 2016
e-pub ahead of print date: 30 September 2016
Published date: 2 December 2016
Organisations:
Faculty of Natural and Environmental Sciences
Identifiers
Local EPrints ID: 404293
URI: http://eprints.soton.ac.uk/id/eprint/404293
ISSN: 0021-9258
PURE UUID: 933e2584-0e38-481a-84b3-96a22426b13b
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Date deposited: 05 Jan 2017 12:23
Last modified: 16 Mar 2024 02:33
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Contributors
Author:
Suzanne G. Mays
Author:
C. Denise Okafor
Author:
Devrishi Goswami
Author:
Jozef Stec
Author:
Autumn R. Flynn
Author:
Michael C. Dugan
Author:
Nathan T. Jui
Author:
Patrick R. Griffin
Author:
Eric A. Ortlund
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