4N5G

Crystal Structure of RXRa LBD complexed with a synthetic modulator K8012

Summary for 4N5G

• Entry DOI: 10.2210/pdb4n5g/pdb
• Descriptor: Retinoic acid receptor RXR-alpha, 5-(2-{(1Z)-5-fluoro-2-methyl-1-[4-(propan-2-yl)benzylidene]-1H-inden-3-yl}ethyl)-1H-tetrazole (3 entities in total)
• Functional Keywords: retinoid x receptor-alpha nuclear receptor, nucleus, signaling protein
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P19793
• Total number of polymer chains: 4
• Total formula weight: 109826.96

Authors

Aleshin, A.E.,Su, Y.,Zhang, X.,Liddington, R.C. (deposition date: 2013-10-09, release date: 2014-05-14, Last modification date: 2024-10-30)

Primary citation

Chen, L.,Wang, Z.G.,Aleshin, A.E.,Chen, F.,Chen, J.,Jiang, F.,Alitongbieke, G.,Zeng, Z.,Ma, Y.,Huang, M.,Zhou, H.,Cadwell, G.,Zheng, J.F.,Huang, P.Q.,Liddington, R.C.,Zhang, X.K.,Su, Y.
Sulindac-Derived RXR alpha Modulators Inhibit Cancer Cell Growth by Binding to a Novel Site.
Chem.Biol., 21:596-607, 2014

PubMed Abstract: Retinoid X receptor-alpha (RXRα), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRα-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRα (tRXRα) with the p85α subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRα modulators and define a binding mechanism for regulating the nongenomic action of tRXRα.

PubMed: 24704507
DOI: 10.1016/j.chembiol.2014.02.017

Experimental method

X-RAY DIFFRACTION (2.11 Å)