3fug | pdb_00003fug
Crystal Structure of the Retinoid X Receptor Ligand Binding Domain Bound to the Synthetic Agonist 3-[4-Hydroxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-phenyl]acrylic Acid
Structural highlights
Disease[NCOA2_HUMAN] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. Function[RXRA_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 RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. 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. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.[1] [2] [3] [4] [NCOA2_HUMAN] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.[5] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedRexinoids are ligands for the retinoid X receptor (RXR) that have great promise for both the prevention and treatment of cancer and metabolic diseases. In this regard, synthetic, functional, and structural investigations into the structure-activity relationships of derivatives of the potent RXR agonist (E)-3-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-hydro xyphenyl]acrylic acid (CD3254, 9) have been conducted. We recently reported on the characterization of a series of C3'-substituted alkyl ether analogues of 9 (10a-f), which display activities ranging from partial agonists to pure antagonists. The importance of the position of the alkoxy side chain for ligand activity has been further explored with the synthesis of C4'-substituted analogues (11a-f). Here we describe the synthesis of compounds 11a-f, which appear functionally different from their isomeric counterparts, as judged from transactivation assays and fluorescence anisotropy experiments. We also report on the 2.0 A resolution structure of RXR in complex with the parent compound 9, which helps understanding of the impact of the alkyl side chain location on ligand activity. Modulating Retinoid X Receptor with a Series of (E)-3-[4-Hydroxy-3-(3-alkoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphtha len-2-yl)phenyl]acrylic Acids and Their 4-Alkoxy Isomers (dagger).,Santin EP, Germain P, Quillard F, Khanwalkar H, Rodriguez-Barrios F, Gronemeyer H, de Lera AR, Bourguet W J Med Chem. 2009 May 1. PMID:19408900[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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