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The Importance of Ligand-Receptor Conformational Pairs in Stabilization: Spotlight on the N/OFQ G Protein-Coupled Receptor
- Publication Year :
- 2015
-
Abstract
- SummaryUnderstanding the mechanism by which ligands affect receptor conformational equilibria is key in accelerating membrane protein structural biology. In the case of G protein-coupled receptors (GPCRs), we currently pursue a brute-force approach for identifying ligands that stabilize receptors and facilitate crystallogenesis. The nociceptin/orphanin FQ peptide receptor (NOP) is a member of the opioid receptor subfamily of GPCRs for which many structurally diverse ligands are available for screening. We observed that antagonist potency is correlated with a ligand's ability to induce receptor stability (Tm) and crystallogenesis. Using this screening strategy, we solved two structures of NOP in complex with top candidate ligands SB-612111 and C-35. Docking studies indicate that while potent, stabilizing antagonists strongly favor a single binding orientation, less potent ligands can adopt multiple binding modes, contributing to their low Tm values. These results suggest a mechanism for ligand-aided crystallogenesis whereby potent antagonists stabilize a single ligand-receptor conformational pair.
- Subjects :
- receptor-ligand conformational pair
medicine.drug_class
Stereochemistry
Molecular Sequence Data
NOP
Nociceptin/orphanin FQ peptide receptor
Ligands
Article
Nociceptin Receptor
BRET
G protein-coupled receptor
GPCR
lipidic cubic phase
membrane protein
N/OFQ
opioid receptor
ORL-1
Molecular Biology
Structural Biology
NO
Piperidines
Opioid receptor
medicine
Humans
Amino Acid Sequence
Cycloheptanes
Binding site
Receptor
Binding Sites
Chemistry
Molecular Docking Simulation
Nociceptin receptor
HEK293 Cells
Structural biology
Docking (molecular)
Receptors, Opioid
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....8ab3202aa1b340bfcd9a0766b7060cb1