5k13
From Proteopedia
Crystal structure of the RAR alpha ligand-binding domain in complex with an antagonist
Structural highlights
DiseaseRARA_HUMAN Note=Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled-coil domain functions in blocking RA-mediated transactivation and cell differentiation. FunctionRARA_HUMAN Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Regulates expression of target genes in a ligand-dependent manner by recruiting chromatin complexes containing MLL5. Mediates retinoic acid-induced granulopoiesis.[1] [2] [3] [4] Publication Abstract from PubMedA series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) alpha, beta and gamma. X-ray crystallography and structure-based drug design were used to improve selectivity for RARgamma by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARgamma potency but were greater than 500-fold selective versus RARalpha and RARbeta. The potent and selective RARgamma antagonist LY2955303 demonstrated good pharmacokinetic properties and was efficacious in the MIA model of osteoarthritis-like joint pain. This compound demonstrated an improved margin to RARalpha-mediated adverse effects. Identification of potent and selective retinoic acid receptor gamma (RARgamma) antagonists for the treatment of osteoarthritis pain using structure based drug design.,Hughes NE, Bleisch TJ, Jones SA, Richardson TI, Doti RA, Wang Y, Stout SL, Durst GL, Chambers MG, Oskins JL, Lin C, Adams LA, Page TJ, Barr RJ, Zink RW, Osborne H, Montrose-Rafizadeh C, Norman BH Bioorg Med Chem Lett. 2016 Jul 15;26(14):3274-7. doi: 10.1016/j.bmcl.2016.05.056., Epub 2016 May 20. PMID:27261179[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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