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PDBsum entry 5nib
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Rar-related orphan receptor-g (rorg)
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PDB id
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5nib
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PDB id:
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| Name: |
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Rar-related orphan receptor-g (rorg)
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Title:
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Ligand complex of rorg lbd
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Structure:
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Nuclear receptor ror-gamma. Chain: a. Synonym: nuclear receptor rzr-gamma,nuclear receptor subfamily 1 group f member 3,rar-related orphan receptor c,retinoid-related orphan receptor-gamma. Engineered: yes. The tethered src2-2 peptide. Chain: c. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: rorc, nr1f3, rorg, rzrg. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
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Resolution:
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1.82Å
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R-factor:
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0.194
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R-free:
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0.227
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Authors:
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Y.Xue,A.Aagaard,F.Narjes
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Key ref:
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F.Narjes
et al.
(2018).
Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design.
J Med Chem,
61,
7796-7813.
PubMed id:
DOI:
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Date:
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23-Mar-17
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Release date:
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22-Aug-18
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PROCHECK
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Headers
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References
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P51449
(RORG_HUMAN) -
Nuclear receptor ROR-gamma from Homo sapiens
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Seq:
Struc:
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518 a.a.
252 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 9 residue positions (black
crosses)
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DOI no:
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J Med Chem
61:7796-7813
(2018)
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PubMed id:
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Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design.
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F.Narjes,
Y.Xue,
S.von Berg,
J.Malmberg,
A.Llinas,
R.I.Olsson,
J.Jirholt,
H.Grindebacke,
A.Leffler,
N.Hossain,
M.Lepistö,
L.Thunberg,
H.Leek,
A.Aagaard,
J.McPheat,
E.L.Hansson,
E.Bäck,
S.Tångefjord,
R.Chen,
Y.Xiong,
G.Hongbin,
T.G.Hansson.
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ABSTRACT
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Retinoic acid receptor related orphan receptor γt (RORγt), has been identified
as the master regulator of TH17-cell function and development, making
it an attractive target for the treatment of autoimmune diseases by a
small-molecule approach. Herein, we describe our investigations on a series of
4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal
structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl
group on the thiophene led to a series of potent binders with nanomolar activity
in a primary human-TH17-cell assay. The observation of a DMSO
molecule binding in a subpocket outside the LBD inspired the introduction of an
acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond
interaction of the introduced acetamide oxygen with the backbone amide of Glu379
was established. This greatly enhanced the cellular activity of previously
weakly cell-active compounds. The best compounds combined potent inhibition of
IL-17 release with favorable PK in rodents, with compound 32 representing a
promising starting point for future investigations.
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