4EA3

Structure of the N/OFQ Opioid Receptor in Complex with a Peptide Mimetic

Summary for 4EA3

• Entry DOI: 10.2210/pdb4ea3/pdb
• Descriptor: Fusion protein of Nociceptin receptor and cytochrome b562, 1-benzyl-N-[3-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)propyl]-D-prolinamide, (2S)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (6 entities in total)
• Functional Keywords: psi-biology gpcr network, structural genomics, gpcr membrane protein 7tm nop orl1 cytochrome b562, receptor, nociceptin orphanin fq compound 24 opioid, fusion, membrane transmembrane, signaling protein
• Biological source: Escherichia coli; More
• Cellular location: Cell membrane; Multi-pass membrane protein: P41146
• Total number of polymer chains: 2
• Total formula weight: 98018.35

Authors

Thompson, A.A.,Liu, W.,Chun, E.,Katritch, V.,Wu, H.,Vardy, E.,Huang, X.P.,Trapella, C.,Guerrini, R.,Calo, G.,Roth, B.L.,Cherezov, V.,Stevens, R.C.,GPCR Network (GPCR) (deposition date: 2012-03-22, release date: 2012-04-25, Last modification date: 2024-11-20)

Primary citation

Thompson, A.A.,Liu, W.,Chun, E.,Katritch, V.,Wu, H.,Vardy, E.,Huang, X.P.,Trapella, C.,Guerrini, R.,Calo, G.,Roth, B.L.,Cherezov, V.,Stevens, R.C.
Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic.
Nature, 485:395-399, 2012

PubMed Abstract: Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, δ, κ and μ (δ-OR, κ-OR and μ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes (∼60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors κ (ref. 5) and μ (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.

PubMed: 22596163
DOI: 10.1038/nature11085

Experimental method

X-RAY DIFFRACTION (3.013 Å)