4M8H

CRYSTAL STRUCTURE OF HUMAN RETINOID X RECEPTOR ALPHA-LIGAND BINDING DOMAIN COMPLEX WITH (R)4-METHYL 9cUAB30 AND COACTIVATOR PEPTIDE GRIP-1

Summary for 4M8H

• Entry DOI: 10.2210/pdb4m8h/pdb
• Related: 3OAP 4K4J 4M8E
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, (2E,6Z,8E)-3,7-dimethyl-8-[(4R)-4-methyl-3,4-dihydronaphthalen-1(2H)-ylidene]octa-2,6-dienoic acid, ... (4 entities in total)
• Functional Keywords: antiparallel sandwich, ligand binding, coactivator binding, dimerization, activation function, transcription, nuclear receptors, ligand binding domain, ligand binding pocket, coactivator binding site, cancer, (r)4-methyl uab30 [(2e, 4e, 6z, 8e)-8-[(4'r)methyl-3', 4'-dihydro-1'(2'h)-naphthalen-1'-ylidene]-3, 7-dimethyl-2, 4, 6-octatrienoic acid]
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P19793 Q15596
• Total number of polymer chains: 2
• Total formula weight: 27613.16

Authors

Xia, G.,Smith, C.D.,Muccio, D.D. (deposition date: 2013-08-13, release date: 2014-01-22, Last modification date: 2023-09-20)

Primary citation

Desphande, A.,Xia, G.,Boerma, L.J.,Vines, K.K.,Atigadda, V.R.,Lobo-Ruppert, S.,Grubbs, C.J.,Moeinpour, F.L.,Smith, C.D.,Christov, K.,Brouillette, W.J.,Muccio, D.D.
Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.
Bioorg.Med.Chem., 22:178-185, 2014

PubMed Abstract: (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.

PubMed: 24359708
DOI: 10.1016/j.bmc.2013.11.039

Experimental method

X-RAY DIFFRACTION (2.2 Å)