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PDBsum entry 5ws3
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Signaling protein
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PDB id
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5ws3
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References listed in PDB file
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Key reference
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Title
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Crystal structures of human orexin 2 receptor bound to the subtype-Selective antagonist empa.
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Authors
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R.Suno,
K.T.Kimura,
T.Nakane,
K.Yamashita,
J.Wang,
T.Fujiwara,
Y.Yamanaka,
D.Im,
S.Horita,
H.Tsujimoto,
M.S.Tawaramoto,
T.Hirokawa,
E.Nango,
K.Tono,
T.Kameshima,
T.Hatsui,
Y.Joti,
M.Yabashi,
K.Shimamoto,
M.Yamamoto,
D.M.Rosenbaum,
S.Iwata,
T.Shimamura,
T.Kobayashi.
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Ref.
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Structure, 2018,
26,
7.
[DOI no: ]
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PubMed id
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Abstract
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Orexin peptides in the brain regulate physiological functions such as the
sleep-wake cycle, and are thus drug targets for the treatment of insomnia. Using
serial femtosecond crystallography and multi-crystal data collection with a
synchrotron light source, we determined structures of human orexin 2 receptor in
complex with the subtype-selective antagonist EMPA
(N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide)
at 2.30-Å and 1.96-Å resolution. In comparison with the non-subtype-selective
antagonist suvorexant, EMPA contacted fewer residues through hydrogen bonds at
the orthosteric site, explaining the faster dissociation rate. Comparisons among
these OX2R structures in complex with selective antagonists and
previously determined OX1R/OX2R structures bound to
non-selective antagonists revealed that the residue at positions 2.61 and 3.33
were critical for the antagonist selectivity in OX2R. The importance
of these residues for binding selectivity to OX2R was also revealed
by molecular dynamics simulation. These results should facilitate the
development of antagonists for orexin receptors.
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