5tbp
Crystal Structure of RXR-alpha ligand binding domain complexed with synthetic modulator K8003
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 PubMedRetinoid X receptor-alpha (RXRalpha) binds to DNA either as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRalpha (tRXRalpha), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85alpha subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXRalpha tetramers via a 'three-pronged' combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXRalpha, owing to the head-tail interaction that is absent in tRXRalpha. We also identify an LxxLL motif in p85alpha, which binds to the coactivator-binding groove on tRXRalpha and dissociates from tRXRalpha upon tRXRalpha tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXRalpha and provide molecular insights into the development of RXRalpha cancer therapeutics. Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXRalpha.,Chen L, Aleshin AE, Alitongbieke G, Zhou Y, Zhang X, Ye X, Hu M, Ren G, Chen Z, Ma Y, Zhang D, Liu S, Gao W, Cai L, Wu L, Zeng Z, Jiang F, Liu J, Zhou H, Cadwell G, Liddington RC, Su Y, Zhang XK Nat Commun. 2017 Jul 17;8:16066. doi: 10.1038/ncomms16066. PMID:28714476[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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