PDBsum entry 6pt2

Membrane protein/agonist

PDB id: 6pt2

Contents

Protein chains

397 a.a.

361 a.a.

Ligands

DI7-DAR-PHE-SAR-OXJ ×2

CLR

OLA ×7

OLC

Waters ×3

PDB id:

6pt2

Name:

Membrane protein/agonist

Title:

Crystal structure of the active delta opioid receptor in complex with the peptide agonist kgchm07

Structure:

Delta opioid receptor. Chain: a, b. Engineered: yes. Peptide agonist kgchm07. Chain: c, d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

2.80Å R-factor: 0.247 R-free: 0.282

Authors:

T.Claff,J.Yu,V.Blais,N.Patel,C.Martin,L.Wu,G.W.Han,B.J.Holleran,O.Van Der Poorten,M.A.Hanson,P.Sarret,L.Gendron,V.Cherezov,V.Katritch, S.Ballet,Z.Liu,C.E.Muller,R.C.Stevens

Key ref:

T.Claff et al. (2019). Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists. Sci Adv, 5, eaax9115. PubMed id: 31807708 DOI: 10.1126/sciadv.aax9115

Date:

14-Jul-19 Release date: 11-Dec-19

Protein chain

P41143  (OPRD_HUMAN) -  Delta-type opioid receptor from Homo sapiens

Seq: 372 a.a.

Struc: 397 a.a.*

Protein chain

P41143  (OPRD_HUMAN) -  Delta-type opioid receptor from Homo sapiens

Seq: 372 a.a.

Struc: 361 a.a.*

* PDB and UniProt seqs differ at 91 residue positions (black crosses)

DOI no: 10.1126/sciadv.aax9115

Sci Adv 5:eaax9115 (2019)

PubMed id: 31807708

Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists.

T.Claff, J.Yu, V.Blais, N.Patel, C.Martin, L.Wu, G.W.Han, B.J.Holleran, O.Van der Poorten, K.L.White, M.A.Hanson, P.Sarret, L.Gendron, V.Cherezov, V.Katritch, S.Ballet, Z.J.Liu, C.E.Müller, R.C.Stevens.

ABSTRACT

Selective activation of the δ-opioid receptor (DOP) has great potential for the treatment of chronic pain, benefitting from ancillary anxiolytic and antidepressant-like effects. Moreover, DOP agonists show reduced adverse effects as compared to μ-opioid receptor (MOP) agonists that are in the spotlight of the current "opioid crisis." Here, we report the first crystal structures of the DOP in an activated state, in complex with two relevant and structurally diverse agonists: the potent opioid agonist peptide KGCHM07 and the small-molecule agonist DPI-287 at 2.8 and 3.3 Å resolution, respectively. Our study identifies key determinants for agonist recognition, receptor activation, and DOP selectivity, revealing crucial differences between both agonist scaffolds. Our findings provide the first investigation into atomic-scale agonist binding at the DOP, supported by site-directed mutagenesis and pharmacological characterization. These structures will underpin the future structure-based development of DOP agonists for an improved pain treatment with fewer adverse effects.