6tlm
From Proteopedia
ROR(gamma)t ligand binding domain in complex with allosteric ligand compound 13 (Glenmark)
Structural highlights
FunctionRORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. Publication Abstract from PubMedThe 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 (RORgammat) 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 RORgammat. A compound library around the central thienopyrazole scaffold captured a clear structure-activity relationship, but the binding mechanism of this new class of RORgammat 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. Elucidation of an allosteric mode-of-action for a thienopyrazole RORgammat inverse agonist.,de Vries RMJM, Meijer FA, Doveston RG, Brunsveld L ChemMedChem. 2020 Feb 13. doi: 10.1002/cmdc.202000044. PMID:32053744[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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