5ZA1

Ligand complex of RORgt LBD

PDB DOI: https://doi.org/10.2210/pdb5ZA1/pdb

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

Deposited: 2018-02-06 Released: 2018-10-31
Deposition Author(s): Yamamoto, S., Yamaguchi, H.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.52 Å
R-Value Free: 0.256
R-Value Work: 0.186
R-Value Observed: 0.190

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (ROR gamma t) inhibitor, S18-000003.

Sasaki, Y., Odan, M., Yamamoto, S., Kida, S., Ueyama, A., Shimizu, M., Haruna, T., Watanabe, A., Okuno, T.

(2018) Bioorg Med Chem Lett 28: 3549-3553

PubMed: 30301676 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2018.09.032
Primary Citation of Related Structures:
5ZA1

PubMed Abstract:
The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, ROR _γt is an attractive drug target for such Th17-mediated autoimmune diseases. A structure-activity relationship (SAR) study of lead compound 1 yielded a novel series of ROR _γt inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable ROR _γt inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.

Organizational Affiliation

Pharmaceutical Research Division, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: yoshikazu.sasaki@shionogi.co.jp.

Macromolecule Content

Total Structure Weight: 56.05 kDa
Atom Count: 3,856
Modelled Residue Count: 454
Deposited Residue Count: 468
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Nuclear receptor ROR-gamma	A, B	234	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 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
9A0 Query on 9A0 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain J [auth B] MOL2 format, chain C [auth A] MOL2 format, chain J [auth B]	C [auth A], J [auth B]	2-[4-({[4-(ethylsulfonyl)phenyl]acetyl}amino)phenyl]-2-methyl-N-phenylpropanamide C₂₆ H₂₈ N₂ O₄ S QECSHZAJHGHAOA-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain J [auth B] Interactions & Density Focus chain C [auth A] Focus chain J [auth B]
DMF Query on DMF Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain O [auth B] MOL2 format, chain I [auth A] MOL2 format, chain O [auth B]	I [auth A], O [auth B]	DIMETHYLFORMAMIDE C₃ H₇ N O ZMXDDKWLCZADIW-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain O [auth B] Interactions & Density Focus chain I [auth A] Focus chain O [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain L [auth B] SDF format, chain M [auth B] SDF format, chain N [auth B] SDF format, chain H [auth A] SDF format, chain K [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain H [auth A] MOL2 format, chain K [auth B]	D [auth A] E [auth A] F [auth A] G [auth A] H [auth A] D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], K [auth B], L [auth B], M [auth B], N [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B]