5x8w
From Proteopedia
Crystal Structure of the mutant Human ROR gamma Ligand Binding Domain.
Structural highlights
Disease[NCOA1_HUMAN] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. Function[NCOA1_HUMAN] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedRetinoid-related orphan receptor gamma (RORgamma) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORgamma, we have determined the first crystal structure of a ternary complex containing RORgamma ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORgamma-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy. Ternary complex of human RORgamma ligand-binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment.,Noguchi M, Nomura A, Murase K, Doi S, Yamaguchi K, Hirata K, Shiozaki M, Hirashima S, Kotoku M, Yamaguchi T, Katsuda Y, Steensma R, Li X, Tao H, Tse B, Fenn M, Babine R, Bradley E, Crowe P, Thacher S, Adachi T, Kamada M Genes Cells. 2017 Jun;22(6):535-551. doi: 10.1111/gtc.12494. Epub 2017 May 11. PMID:28493531[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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