6PT3

Crystal structure of the active delta opioid receptor in complex with the small molecule agonist DPI-287

Summary for 6PT3

• Entry DOI: 10.2210/pdb6pt3/pdb
• Descriptor: Delta opioid receptor, 4-[(R)-[(2S,5R)-4-benzyl-2,5-dimethylpiperazin-1-yl](3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (2 entities in total)
• Functional Keywords: membrane protein, g protein-coupled receptor, gpcr, dop, dor, agonist, active dop-dpi-287 structure, lcp, membrane protein-agonist complex, membrane protein/agonist
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 103089.52

Authors

Claff, T.,Yu, J.,Blais, V.,Patel, N.,Martin, C.,Wu, L.,Han, G.W.,Holleran, B.J.,Van der Poorten, O.,Hanson, M.A.,Sarret, P.,Gendron, L.,Cherezov, V.,Katritch, V.,Ballet, S.,Liu, Z.,Muller, C.E.,Stevens, R.C. (deposition date: 2019-07-14, release date: 2019-12-11, Last modification date: 2024-11-06)

Primary citation

Claff, T.,Yu, J.,Blais, V.,Patel, N.,Martin, C.,Wu, L.,Han, G.W.,Holleran, B.J.,Van der Poorten, O.,White, K.L.,Hanson, M.A.,Sarret, P.,Gendron, L.,Cherezov, V.,Katritch, V.,Ballet, S.,Liu, Z.J.,Muller, C.E.,Stevens, R.C.
Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists.
Sci Adv, 5:eaax9115-eaax9115, 2019

PubMed 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.

PubMed: 31807708
DOI: 10.1126/sciadv.aax9115

Experimental method

X-RAY DIFFRACTION (3.3 Å)