5W4V

Structure of RORgt bound to a tertiary alcohol

Summary for 5W4V

• Entry DOI: 10.2210/pdb5w4v/pdb
• Related: 5W4R
• Descriptor: Nuclear receptor ROR-gamma, (R)-(4-chloro-2-methoxy-3-{[4-(1H-pyrazol-1-yl)phenyl]methyl}quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol (3 entities in total)
• Functional Keywords: rorgt nuclear hormone receptor, nuclear protein
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P51449
• Total number of polymer chains: 6
• Total formula weight: 150680.13

Authors

Spurlino, J.,Hars, U. (deposition date: 2017-06-13, release date: 2017-12-27, Last modification date: 2023-10-04)

Primary citation

Barbay, J.K.,Cummings, M.D.,Abad, M.,Castro, G.,Kreutter, K.D.,Kummer, D.A.,Maharoof, U.,Milligan, C.,Nishimura, R.,Pierce, J.,Schalk-Hihi, C.,Spurlino, J.,Tanis, V.M.,Urbanski, M.,Venkatesan, H.,Wang, A.,Woods, C.,Wolin, R.,Xue, X.,Edwards, J.P.,Fourie, A.M.,Leonard, K.
6-Substituted quinolines as ROR gamma t inverse agonists.
Bioorg. Med. Chem. Lett., 27:5277-5283, 2017

PubMed Abstract: We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). The synthesis of this class of RORγt modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a RORγt-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORγt ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact.

PubMed: 29079472
DOI: 10.1016/j.bmcl.2017.10.027

Experimental method

X-RAY DIFFRACTION (2.65 Å)