3g8i
From Proteopedia
Aleglitazar, a new, potent, and balanced PPAR alpha/gamma agonist for the treatment of type II diabetes
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[PPARA_HUMAN] Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety (By similarity). Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2.[1] [2] [3] [4] [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.[5] [6] [7] [8] [9] [10] [11] 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 PubMedDesign, synthesis, and SAR of novel alpha-alkoxy-beta-arylpropionic acids as potent and balanced PPARalphagamma coagonists are described. One representative thereof, Aleglitazar ((S)-2Aa), was chosen for clinical development. Its X-ray structure in complex with both receptors as well as its high efficacy in animal models of T2D and dyslipidemia are also presented. Aleglitazar, a new, potent, and balanced dual PPARalpha/gamma agonist for the treatment of type II diabetes.,Benardeau A, Benz J, Binggeli A, Blum D, Boehringer M, Grether U, Hilpert H, Kuhn B, Marki HP, Meyer M, Puntener K, Raab S, Ruf A, Schlatter D, Mohr P Bioorg Med Chem Lett. 2009 May 1;19(9):2468-73. Epub 2009 Mar 14. PMID:19349176[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||||||
Categories: Histone acetyltransferase | Homo sapiens | Benz, J | Bernardeau, A | Binggeli, A | Blum, D | Boehringer, M | Grether, U | Gsell, B | Hilpert, H | Kuhn, B | Maerki, H P | Meyer, M | Mohr, P | Puentener, K | Raab, S | Ruf, A | Schlatter, D | Stihle, M | Activator | Acyltransferase | Diabetes | Dna-binding | Metal-binding | Nuclear hormone receptor | Nucleus | Phosphoprotein | Proto-oncogene | Receptor | Transcription | Transcription factor | Transcription regulation | Transcription-transferase complex | Transferase | Zinc-finger
