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Orphan nuclear receptors adopted by crystallography
Holly A Ingraham1, Matthew R Redinbo
1Department of Physiology, 1550 4(th) Street, University of California, San Francisco, Box 2611, Mission Bay Campus, San Francisco, CA 94143-2611, USA. holly.ingraham@ucsf.edu
Current Opinion in Structural Biology
|November 3, 2005
Summary
Structural biology reveals orphan nuclear receptors are not always ligand-free. Their regulation varies from ligand-independent to highly ligand-dependent, with diverse ligand-binding pocket sizes and activities.
Area of Science:
- Molecular biology
- Structural biology
- Endocrinology
Background:
- Orphan nuclear receptors (ONRs) are part of a large protein superfamily, historically mysterious due to unidentified ligands and constitutive activity.
- Previous molecular studies offered limited insights into ONR regulation and function.
Purpose of the Study:
- To elucidate the structural and functional characteristics of orphan nuclear receptors.
- To understand the diverse regulatory mechanisms of formerly orphan nuclear receptors.
Main Methods:
- X-ray crystallography to determine the structures of ligand-binding domains of several orphan nuclear receptors.
- Molecular and cellular physiology studies to assess receptor activity and ligand-binding properties.
Main Results:
- Structural data revealed significant diversity in ligand-binding pocket volumes, ranging from >1600ų to non-existent.
- Orphan nuclear receptors exhibit varied surface AF2 (activation function 2) motif activities, from multifunctional to inactive.
- Many previously orphan receptors have been 'adopted,' showing regulation from ligand-independent to highly promiscuous ligand-dependent.
Conclusions:
- Structural biology provides crucial insights into orphan nuclear receptor function, complementing molecular studies.
- The diverse structural features of orphan nuclear receptors explain their varied regulatory mechanisms.
- Understanding these receptors is key to deciphering complex cellular physiology and endocrine signaling pathways.