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PDBsum entry 4wpf
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Transcription
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PDB id
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4wpf
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References listed in PDB file
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Key reference
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Title
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Minor structural change to tertiary sulfonamide rorc ligands led to opposite mechanisms of action.
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Authors
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O.René,
B.P.Fauber,
G.D.E. .L.Boenig,
B.Burton,
C.Eidenschenk,
C.Everett,
A.Gobbi,
S.G.Hymowitz,
A.R.Johnson,
J.R.Kiefer,
M.Liimatta,
P.Lockey,
M.Norman,
W.Ouyang,
H.A.Wallweber,
H.Wong.
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Ref.
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Acs Med Chem Lett, 2015,
6,
276-281.
[DOI no: ]
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PubMed id
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Abstract
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A minor structural change to tertiary sulfonamide RORc ligands led to distinct
mechanisms of action. Co-crystal structures of two compounds revealed
mechanistically consistent protein conformational changes. Optimized
phenylsulfonamides were identified as RORc agonists while benzylsulfonamides
exhibited potent inverse agonist activity. Compounds behaving as agonists in our
biochemical assay also gave rise to an increased production of IL-17 in human
PBMCs whereas inverse agonists led to significant suppression of IL-17 under the
same assay conditions. The most potent inverse agonist compound showed
>180-fold selectivity over the ROR isoforms as well as all other nuclear
receptors that were profiled.
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