6cn6

From Proteopedia

(Difference between revisions)

Current revision

RORC2 LBD complexed with compound 34

Structural highlights

6cn6 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.45Å
Ligands:
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.

Publication Abstract from PubMed

The nuclear hormone receptor RORC2 (also known as RORgammat) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key pro-inflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

Discovery of 3-Cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)benzamide. A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 (RORC2) Inverse Agonist.,Schnute ME, Wennerstal M, Alley J, Bengtsson M, Blinn JR, Bolten CW, Braden T, Bonn T, Carlsson B, Caspers NL, Chen MZ, Choi C, Collis LP, Crouse K, F Auml Rneg Aring Rdh M, Fennell KF, Fish S, Flick A, Goos-Nilsson A, Gullberg H, Harris PK, Heasley SE, Hegen M, Hromockyj AE, Hu X, Husman B, Janosik T, Jones P, Kaila N, Kallin E, Kauppi B, Kiefer JR, Knafels JD, Koehler K, Kruger L, Kurumbail RG, Kyne RE Jr, Li W, Lofstedt J, Long SA, Menard CA, Mente S, Messing D, Meyers MJ, Napierata L, Noteberg D, Nuhant P, Pelc MJ, Prinsen MJ, Rhonnstad P, Backstrom-Rydin E, Sandberg J, Sandstrom M, Shah F, Sjoberg M, Sundell A, Taylor AP, Thorarensen A, Trujillo JI, Trzupek JD, Unwalla R, Vajdos FF, Weinberg RA, Wood DC, Xing L, Zamaratski E, Zapf CW, Zhao Y, Wilhelmsson A, Berstein G J Med Chem. 2018 Aug 21. doi: 10.1021/acs.jmedchem.8b00392. PMID:30130103^[1]

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

References

↑ Schnute ME, Wennerstal M, Alley J, Bengtsson M, Blinn JR, Bolten CW, Braden T, Bonn T, Carlsson B, Caspers NL, Chen MZ, Choi C, Collis LP, Crouse K, F Auml Rneg Aring Rdh M, Fennell KF, Fish S, Flick A, Goos-Nilsson A, Gullberg H, Harris PK, Heasley SE, Hegen M, Hromockyj AE, Hu X, Husman B, Janosik T, Jones P, Kaila N, Kallin E, Kauppi B, Kiefer JR, Knafels JD, Koehler K, Kruger L, Kurumbail RG, Kyne RE Jr, Li W, Lofstedt J, Long SA, Menard CA, Mente S, Messing D, Meyers MJ, Napierata L, Noteberg D, Nuhant P, Pelc MJ, Prinsen MJ, Rhonnstad P, Backstrom-Rydin E, Sandberg J, Sandstrom M, Shah F, Sjoberg M, Sundell A, Taylor AP, Thorarensen A, Trujillo JI, Trzupek JD, Unwalla R, Vajdos FF, Weinberg RA, Wood DC, Xing L, Zamaratski E, Zapf CW, Zhao Y, Wilhelmsson A, Berstein G. Discovery of 3-Cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)benzamide. A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 (RORC2) Inverse Agonist. J Med Chem. 2018 Aug 21. doi: 10.1021/acs.jmedchem.8b00392. PMID:30130103 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00392

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6cn6"

Categories: Homo sapiens | Large Structures | Kauppi B | Vajdos F

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6cn6 is ON HOLD  until Paper Publication
+==RORC2 LBD complexed with compound 34==
+<StructureSection load='6cn6' size='340' side='right'caption='[[6cn6]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6cn6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CN6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CN6 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.45&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F7J:3-cyano-~{N}-[3-(1-cyclopentylcarbonylpiperidin-4-yl)-1,4-dimethyl-indol-5-yl]benzamide'>F7J</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6cn6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cn6 OCA], [https://pdbe.org/6cn6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cn6 RCSB], [https://www.ebi.ac.uk/pdbsum/6cn6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cn6 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/RORG_HUMAN 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.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The nuclear hormone receptor RORC2 (also known as RORgammat) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key pro-inflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.
-Authors: Kauppi, B., Vajdos, F.
+Discovery of 3-Cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)benzamide. A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 (RORC2) Inverse Agonist.,Schnute ME, Wennerstal M, Alley J, Bengtsson M, Blinn JR, Bolten CW, Braden T, Bonn T, Carlsson B, Caspers NL, Chen MZ, Choi C, Collis LP, Crouse K, F Auml Rneg Aring Rdh M, Fennell KF, Fish S, Flick A, Goos-Nilsson A, Gullberg H, Harris PK, Heasley SE, Hegen M, Hromockyj AE, Hu X, Husman B, Janosik T, Jones P, Kaila N, Kallin E, Kauppi B, Kiefer JR, Knafels JD, Koehler K, Kruger L, Kurumbail RG, Kyne RE Jr, Li W, Lofstedt J, Long SA, Menard CA, Mente S, Messing D, Meyers MJ, Napierata L, Noteberg D, Nuhant P, Pelc MJ, Prinsen MJ, Rhonnstad P, Backstrom-Rydin E, Sandberg J, Sandstrom M, Shah F, Sjoberg M, Sundell A, Taylor AP, Thorarensen A, Trujillo JI, Trzupek JD, Unwalla R, Vajdos FF, Weinberg RA, Wood DC, Xing L, Zamaratski E, Zapf CW, Zhao Y, Wilhelmsson A, Berstein G J Med Chem. 2018 Aug 21. doi: 10.1021/acs.jmedchem.8b00392. PMID:30130103<ref>PMID:30130103</ref>
-Description: RORC2 LBD complexed with compound 34
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Vajdos, F]]
+<div class="pdbe-citations 6cn6" style="background-color:#fffaf0;"></div>
-[[Category: Kauppi, B]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Kauppi B]]
+[[Category: Vajdos F]]

6cn6

From Proteopedia

Current revision

RORC2 LBD complexed with compound 34

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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