6PT2

Crystal structure of the active delta opioid receptor in complex with the peptide agonist KGCHM07

6PT2 の概要

• エントリーDOI: 10.2210/pdb6pt2/pdb
• 分子名称: Delta opioid receptor, Peptide agonist KGCHM07, CHOLESTEROL, ... (6 entities in total)
• 機能のキーワード: membrane protein, g protein-coupled receptor, gpcr, dop, dor, peptide agonist, active dop-kgchm07 structure, lcp, membrane protein-agonist complex, membrane protein/agonist
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 106486.31

構造登録者

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. (登録日: 2019-07-14, 公開日: 2019-12-11, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.8 Å)