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PDBsum entry 6pt2
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Membrane protein/agonist
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PDB id
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6pt2
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References listed in PDB file
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Key reference
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Title
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Elucidating the active δ-Opioid receptor crystal structure with peptide and small-Molecule agonists.
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Authors
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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.
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Ref.
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Sci Adv, 2019,
5,
eaax9115.
[DOI no: ]
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PubMed id
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Abstract
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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.
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