6B30

Structure of RORgt in complex with a novel inverse agonist 1

PDB DOI: https://doi.org/10.2210/pdb6B30/pdb

Classification: SIGNALING PROTEIN
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2017-09-20 Released: 2018-01-03
Deposition Author(s): Skene, R.J., Hoffman, I.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.69 Å
R-Value Free: 0.234
R-Value Work: 0.189
R-Value Observed: 0.191

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Discovery of orally efficacious ROR gamma t inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds.

Shirai, J., Tomata, Y., Kono, M., Ochida, A., Fukase, Y., Sato, A., Masada, S., Kawamoto, T., Yonemori, K., Koyama, R., Nakagawa, H., Nakayama, M., Uga, K., Shibata, A., Koga, K., Okui, T., Shirasaki, M., Skene, R., Sang, B., Hoffman, I., Lane, W., Fujitani, Y., Yamasaki, M., Yamamoto, S.

(2018) Bioorg Med Chem 26: 483-500

PubMed: 29262987 Search on PubMed
DOI: https://doi.org/10.1016/j.bmc.2017.12.006
Primary Citation of Related Structures:
6B30

PubMed Abstract:
A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.

Organizational Affiliation

Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: junya.shirai@cardurion.com.

Macromolecule Content

Total Structure Weight: 50.91 kDa
Atom Count: 3,586
Modelled Residue Count: 427
Deposited Residue Count: 430
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Nuclear receptor ROR-gamma	A, B	215	Homo sapiens	Mutation(s): 0 Gene Names: RORC, NR1F3, RORG, RZRG
UniProt & NIH Common Fund Data Resources
Find proteins for P51449 (Homo sapiens) Explore P51449 Go to UniProtKB: P51449
PHAROS: P51449 GTEx: ENSG00000143365
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P51449
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
CFG Query on CFG Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth B]	C [auth A], D [auth B]	N-[(1R)-1-(4-methoxyphenyl)-2-oxo-2-{[4-(trimethylsilyl)phenyl]amino}ethyl]-N-methyl-3-oxo-2,3-dihydro-1,2-oxazole-5-carboxamide C₂₃ H₂₇ N₃ O₅ Si RQLIWGALGGOPGM-OAQYLSRUSA-N		Interactions Focus chain C [auth A] Focus chain D [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth B]