5DHH

The crystal structure of nociceptin/orphanin FQ peptide receptor (NOP) in complex with SB-612111 (PSI Community Target)

Summary for 5DHH

• Entry DOI: 10.2210/pdb5dhh/pdb
• Related: 4EA3
• Descriptor: Soluble cytochrome b562,Nociceptin receptor, OLEIC ACID, (5S,7S)-7-{[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl}-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol, ... (4 entities in total)
• Functional Keywords: nociceptin/orphanin fq peptide receptor, nop, orl-1, n/ofq, opioid receptor, g protein-coupled receptor, gpcr, membrane protein, lipidic cubic phase, bret, receptor-ligand conformational pair, structural genomics, psi-biology, gpcr network, signaling protein, psicnt-127
• Biological source: Escherichia coli; More
• Cellular location: Cell membrane; Multi-pass membrane protein: P41146
• Total number of polymer chains: 2
• Total formula weight: 96563.31

Authors

Miller, R.L.,Thompson, A.A.,Trapella, C.,Guerrini, R.,Malfacini, D.,Patel, N.,Han, G.W.,Cherezov, V.,Calo, G.,Katritch, V.,Stevens, R.C.,GPCR Network (GPCR) (deposition date: 2015-08-31, release date: 2015-10-21, Last modification date: 2024-10-23)

Primary citation

Miller, R.L.,Thompson, A.A.,Trapella, C.,Guerrini, R.,Malfacini, D.,Patel, N.,Han, G.W.,Cherezov, V.,Calo, G.,Katritch, V.,Stevens, R.C.
The Importance of Ligand-Receptor Conformational Pairs in Stabilization: Spotlight on the N/OFQ G Protein-Coupled Receptor.
Structure, 23:2291-2299, 2015

PubMed Abstract: Understanding 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.

PubMed: 26526853
DOI: 10.1016/j.str.2015.07.024

Experimental method

X-RAY DIFFRACTION (3.004 Å)