4N6H

1.8 A Structure of the human delta opioid 7TM receptor (PSI Community Target)

Summary for 4N6H

• Entry DOI: 10.2210/pdb4n6h/pdb
• Related: 4EJ4
• Descriptor: Soluble cytochrome b562, Delta-type opioid receptor chimeric protein, OLEIC ACID, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (8 entities in total)
• Functional Keywords: human opioid receptor, sodium regulation, allostery, functional selectivity, gpcr signaling, constitutive activity, gpcr network, membrane protein, psi-biology, structural genomics, gpcr, membrane, signaling protein
• Biological source: Escherichia coli (human); More
• Cellular location: Cell membrane ; Multi- pass membrane protein : P41143
• Total number of polymer chains: 1
• Total formula weight: 52088.38

Authors

Fenalti, G.,Giguere, P.M.,Katritch, V.,Huang, X.-P.,Thompson, A.A.,Han, G.W.,Cherezov, V.,Roth, B.L.,Stevens, R.C.,GPCR Network (GPCR) (deposition date: 2013-10-12, release date: 2013-12-25, Last modification date: 2024-10-16)

Primary citation

Fenalti, G.,Giguere, P.M.,Katritch, V.,Huang, X.P.,Thompson, A.A.,Cherezov, V.,Roth, B.L.,Stevens, R.C.
Molecular control of delta-opioid receptor signalling.
Nature, 506:191-196, 2014

PubMed Abstract: Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 Å high-resolution crystal structure of the human δ-opioid receptor (δ-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive δ-OR sodium ion site architecture is centrally located in a polar interaction network in the seven-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn 131 to an alanine or a valine augments constitutive β-arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical δ-opioid antagonists such as naltrindole into potent β-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G-protein-coupled receptor.

PubMed: 24413399
DOI: 10.1038/nature12944

Experimental method

X-RAY DIFFRACTION (1.8 Å)