6g05 | pdb_00006g05

RORGT (264-518;C455S) IN COMPLEX WITH INVERSE AGONIST "CPD-2" AND RIP140 PEPTIDE AT 1.90A

Structural highlights

6g05 is a 4 chain structure with sequence from Human and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	EF5
Related:	6fzu
Gene:	RORC, NR1F3, RORG, RZRG (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. [NRIP1_HUMAN] Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1. Also modulates transcriptional repression by nuclear hormone receptors.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

The transcription factor RORgammat is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORgammat inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism. In contrast to other reported inverse agonists, there is no direct interaction or displacement of helix 12 observed in the crystal structure. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats.

Optimizing a weakly binding fragment into a potent RORgammat inverse agonist with efficacy in an in vivo inflammation model.,Carcache D, Vulpetti A, Kallen J, Mattes H, Orain D, Stringer R, Vangrevelinghe E, Wolf RM, Kaupmann K, Ottl J, Dawson King J, Cooke NG, Hoegenauer K, Billich A, Wagner J, Guntermann C, Hintermann S J Med Chem. 2018 Jul 10. doi: 10.1021/acs.jmedchem.8b00529. PMID:29990434^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cavailles V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 1995 Aug 1;14(15):3741-51. PMID:7641693
↑ Subramaniam N, Treuter E, Okret S. Receptor interacting protein RIP140 inhibits both positive and negative gene regulation by glucocorticoids. J Biol Chem. 1999 Jun 18;274(25):18121-7. PMID:10364267
↑ Vo N, Fjeld C, Goodman RH. Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP. Mol Cell Biol. 2001 Sep;21(18):6181-8. PMID:11509661
↑ Zennaro MC, Souque A, Viengchareun S, Poisson E, Lombes M. A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action. Mol Endocrinol. 2001 Sep;15(9):1586-98. PMID:11518808
↑ Teyssier C, Belguise K, Galtier F, Cavailles V, Chalbos D. Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect. Mol Endocrinol. 2003 Feb;17(2):287-99. PMID:12554755 doi:https://dx.doi.org/10.1210/me.2002-0324
↑ Castet A, Boulahtouf A, Versini G, Bonnet S, Augereau P, Vignon F, Khochbin S, Jalaguier S, Cavailles V. Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition. Nucleic Acids Res. 2004 Apr 1;32(6):1957-66. Print 2004. PMID:15060175 doi:https://dx.doi.org/10.1093/nar/gkh524
↑ Carcache D, Vulpetti A, Kallen J, Mattes H, Orain D, Stringer R, Vangrevelinghe E, Wolf RM, Kaupmann K, Ottl J, Dawson King J, Cooke NG, Hoegenauer K, Billich A, Wagner J, Guntermann C, Hintermann S. Optimizing a weakly binding fragment into a potent RORgammat inverse agonist with efficacy in an in vivo inflammation model. J Med Chem. 2018 Jul 10. doi: 10.1021/acs.jmedchem.8b00529. PMID:29990434 doi:https://dx.doi.org/10.1021/acs.jmedchem.8b00529

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Cavailles V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 1995 Aug 1;14(15):3741-51. PMID:7641693

[2] Subramaniam N, Treuter E, Okret S. Receptor interacting protein RIP140 inhibits both positive and negative gene regulation by glucocorticoids. J Biol Chem. 1999 Jun 18;274(25):18121-7. PMID:10364267

[3] Vo N, Fjeld C, Goodman RH. Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP. Mol Cell Biol. 2001 Sep;21(18):6181-8. PMID:11509661

[4] Zennaro MC, Souque A, Viengchareun S, Poisson E, Lombes M. A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action. Mol Endocrinol. 2001 Sep;15(9):1586-98. PMID:11518808

[5] Teyssier C, Belguise K, Galtier F, Cavailles V, Chalbos D. Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect. Mol Endocrinol. 2003 Feb;17(2):287-99. PMID:12554755 doi:https://dx.doi.org/10.1210/me.2002-0324

[6] Castet A, Boulahtouf A, Versini G, Bonnet S, Augereau P, Vignon F, Khochbin S, Jalaguier S, Cavailles V. Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition. Nucleic Acids Res. 2004 Apr 1;32(6):1957-66. Print 2004. PMID:15060175 doi:https://dx.doi.org/10.1093/nar/gkh524

[7] Carcache D, Vulpetti A, Kallen J, Mattes H, Orain D, Stringer R, Vangrevelinghe E, Wolf RM, Kaupmann K, Ottl J, Dawson King J, Cooke NG, Hoegenauer K, Billich A, Wagner J, Guntermann C, Hintermann S. Optimizing a weakly binding fragment into a potent RORgammat inverse agonist with efficacy in an in vivo inflammation model. J Med Chem. 2018 Jul 10. doi: 10.1021/acs.jmedchem.8b00529. PMID:29990434 doi:https://dx.doi.org/10.1021/acs.jmedchem.8b00529

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6g05 | pdb_00006g05

RORGT (264-518;C455S) IN COMPLEX WITH INVERSE AGONIST "CPD-2" AND RIP140 PEPTIDE AT 1.90A

Structural highlights

Function

Publication Abstract from PubMed

References

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