5TBP

Crystal Structure of RXR-alpha ligand binding domain complexed with synthetic modulator K8003

Summary for 5TBP

• Entry DOI: 10.2210/pdb5tbp/pdb
• Descriptor: Retinoic acid receptor RXR-alpha, [(1Z)-5-fluoro-2-methyl-1-{[4-(propan-2-yl)phenyl]methylidene}-1H-inden-3-yl]acetic acid, ACETATE ION, ... (6 entities in total)
• Functional Keywords: nuclear receptor, sulindac, akt activation, complex, tetramer, transcription, rxr, lbd
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 111772.08

Authors

Aleshin, A.E.,Liddington, R.C.,Su, Y.,Zhang, X. (deposition date: 2016-09-12, release date: 2017-08-09, Last modification date: 2024-10-09)

Primary citation

Chen, L.,Aleshin, A.E.,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, R.C.,Su, Y.,Zhang, X.K.
Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXR alpha.
Nat Commun, 8:16066-16066, 2017

PubMed Abstract: Retinoid X receptor-alpha (RXRα) 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 RXRα (tRXRα), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85α 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 tRXRα tetramers via a 'three-pronged' combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXRα, owing to the head-tail interaction that is absent in tRXRα. We also identify an LxxLL motif in p85α, which binds to the coactivator-binding groove on tRXRα and dissociates from tRXRα upon tRXRα tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXRα and provide molecular insights into the development of RXRα cancer therapeutics.

PubMed: 28714476
DOI: 10.1038/ncomms16066

Experimental method

X-RAY DIFFRACTION (2.6 Å)