6E3G

Structure of RORgt in complex with a novel agonist.

Summary for 6E3G

• Entry DOI: 10.2210/pdb6e3g/pdb
• Descriptor: Nuclear receptor ROR-gamma, co-activator peptide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: nuclear hormone receptor, agonist, nuclear protein, nuclear protein-agonist complex, nuclear protein/agonist
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 60229.96

Authors

Skene, R.J.,Hoffman, I. (deposition date: 2018-07-13, release date: 2019-06-12, Last modification date: 2024-03-13)

Primary citation

Yukawa, T.,Nara, Y.,Kono, M.,Sato, A.,Oda, T.,Takagi, T.,Sato, T.,Banno, Y.,Taya, N.,Imada, T.,Shiokawa, Z.,Negoro, N.,Kawamoto, T.,Koyama, R.,Uchiyama, N.,Skene, R.,Hoffman, I.,Chen, C.H.,Sang, B.,Snell, G.,Katsuyama, R.,Yamamoto, S.,Shirai, J.
Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor gamma t (ROR gamma t) Agonist Structure-Based Functionality Switching Approach from In House ROR gamma t Inverse Agonist to ROR gamma t Agonist.
J.Med.Chem., 62:1167-1179, 2019

PubMed Abstract: Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation of Th17 cells and Tc17 cells. Herein, we describe a novel structure-based functionality switching approach from in house well-optimized RORγt inverse agonists to potent RORγt agonists. We succeeded in the identification of potent RORγt agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed a helix 12 stabilization effect of RORγt agonists. These results indicate that targeting helix 12 is an attractive and novel medicinal chemistry strategy for switching existing RORγt inverse agonists to agonists.

PubMed: 30652849
DOI: 10.1021/acs.jmedchem.8b01181

Experimental method

X-RAY DIFFRACTION (2.1 Å)