6a22 | pdb_00006a22
Ternary complex of Human ROR gamma Ligand Binding Domain With Compound T.
Structural highlights
Function[RORG_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. [NCOR2_HUMAN] Transcriptional corepressor of NR4A2/NURR1 and acts through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1 target genes in a repressed deacetylated state (By similarity). Mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access of the basal transcription. Isoform 1 and isoform 5 have different affinities for different nuclear receptors. Publication Abstract from PubMedRetinoic acid-related orphan receptor gamma (RORgamma) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4(+) T cells (Th17 cells). Structure-based drug design has proven fruitful in the development of inhibitors targeting the ligand binding domain (LBD) of RORgamma. Here, we present the crystal structure of a novel RORgamma inhibitor co-complex, in the presence of a corepressor (CoR) peptide. This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 A shift of helix 5 (H5) backbone and side-chain conformational changes of Met365 on H5. These conformational changes correlate to reduced CoR peptide binding to RORgamma-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders. Ternary crystal structure of human RORgamma ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction.,Noguchi M, Nomura A, Doi S, Yamaguchi K, Hirata K, Shiozaki M, Maeda K, Hirashima S, Kotoku M, Yamaguchi T, Katsuda Y, Crowe P, Tao H, Thacher S, Adachi T Sci Rep. 2018 Nov 26;8(1):17374. doi: 10.1038/s41598-018-35783-9. PMID:30478402[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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