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Crystal structure of tetrameric RXRalpha-LBD complexed with partial agonist CBt-PMN
Structural highlights
FunctionRXRA_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] Publication Abstract from PubMed1-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5 -carboxylic acid (CBt-PMN), a partial agonist of retinoid X receptor (RXR), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of existing full agonists. Herein, we report the crystal structure of CBt-PMN-bound ligand-binding domain of human RXRalpha (hRXRalpha) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt-PMNs are clearly found binding in two different conformations. The dynamics of the hRXRalpha/CBt-PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF-2 interface depends on the conformation of the ligand. These facts reveal that the dual conformation of CBt-PMN in the complex is probably the reason behind its partial agonistic activity. Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor alpha (RXRalpha).,Miyashita Y, Numoto N, Arulmozhiraja S, Nakano S, Matsuo N, Shimizu K, Shibahara O, Fujihara M, Kakuta H, Ito S, Ikura T, Ito N, Tokiwa H FEBS Lett. 2019 Jan;593(2):242-250. doi: 10.1002/1873-3468.13301. Epub 2018 Dec, 21. PMID:30565665[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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