7bpz
X-ray structure of human PPARalpha ligand binding domain-bezafibrate-SRC1 coactivator peptide co-crystals obtained by soaking
Structural highlights
DiseaseNCOA1_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. FunctionNCOA1_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 PubMedMost triacylglycerol-lowering fibrates have been developed in the 1960s-1980s before their molecular target, peroxisome proliferator-activated receptor alpha (PPARalpha), was identified. Twenty-one ligand-bound PPARalpha structures have been deposited in the Protein Data Bank since 2001; however, binding modes of fibrates and physiological ligands remain unknown. Here we show thirty-four X-ray crystallographic structures of the PPARalpha ligand-binding domain, which are composed of a "Center" and four "Arm" regions, in complexes with five endogenous fatty acids, six fibrates in clinical use, and six synthetic PPARalpha agonists. High-resolution structural analyses, in combination with coactivator recruitment and thermostability assays, demonstrate that stearic and palmitic acids are presumably physiological ligands; coordination to Arm III is important for high PPARalpha potency/selectivity of pemafibrate and GW7647; and agonistic activities of four fibrates are enhanced by the partial agonist GW9662. These results renew our understanding of PPARalpha ligand recognition and contribute to the molecular design of next-generation PPAR-targeted drugs. PPARalpha Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates.,Kamata S, Oyama T, Saito K, Honda A, Yamamoto Y, Suda K, Ishikawa R, Itoh T, Watanabe Y, Shibata T, Uchida K, Suematsu M, Ishii I iScience. 2020 Oct 23;23(11):101727. doi: 10.1016/j.isci.2020.101727. eCollection, 2020 Nov 20. PMID:33205029[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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