6TLM
ROR(gamma)t ligand binding domain in complex with allosteric ligand compound 13 (Glenmark)
Summary for 6TLM
| Entry DOI | 10.2210/pdb6tlm/pdb |
| Descriptor | Nuclear receptor ROR-gamma, 4-[1-[2,6-bis(chloranyl)phenyl]carbonyl-5-methyl-thieno[3,2-c]pyrazol-3-yl]benzoic acid (3 entities in total) |
| Functional Keywords | nuclear receptor, allosteric, inverse agonist, inhibitor, gene regulation |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 30945.46 |
| Authors | de Vries, R.M.J.M.,Meijer, F.A.,Brunsveld, L. (deposition date: 2019-12-03, release date: 2020-03-04, Last modification date: 2024-01-24) |
| Primary citation | de Vries, R.M.J.M.,Doveston, R.G.,Meijer, F.A.,Brunsveld, L. Elucidation of an Allosteric Mode of Action for a Thienopyrazole ROR gamma t Inverse Agonist. Chemmedchem, 15:561-565, 2020 Cited by PubMed Abstract: The demand for allosteric targeting of nuclear receptors is high, but examples are limited, and structural information is scarce. The retinoic acid-related orphan receptor gamma t (RORγt) is an important transcriptional regulator for the differentiation of T helper 17 cells for which the first, and some of the most promising, examples of allosteric nuclear receptor modulation have been reported and structurally proven. In a 2015 patent, filed by the pharmaceutical company Glenmark, a new class of small molecules was reported that act as potent inverse agonists for RORγt. A compound library around the central thienopyrazole scaffold captured a clear structure-activity relationship, but the binding mechanism of this new class of RORγt modulators has not been elucidated. Using a combination of biochemical and X-ray crystallography studies, here the allosteric mechanism for the inverse agonism for the most potent compound, classified in the patent as "example 13", is reported, providing a strongly desired additional example of allosteric nuclear receptor targeting. PubMed: 32053744DOI: 10.1002/cmdc.202000044 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.321 Å) |
Structure validation
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