4RMC

Crystal Structure of human retinoid X receptor alpha-ligand binding domain complex with 9cUAB76 and the coactivator peptide GRIP-1

Summary for 4RMC

• Entry DOI: 10.2210/pdb4rmc/pdb
• Related: 3OAP 4K4J
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, (3S,7S,8E)-8-[3-ethyl-2-(3-methylbutyl)cyclohex-2-en-1-ylidene]-3,7-dimethyloctanoic acid, ... (4 entities in total)
• Functional Keywords: ligand binding domain, cancer prevention, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : P19793 Q15596
• Total number of polymer chains: 2
• Total formula weight: 27825.45

Authors

Xia, G.,Muccio, D.D. (deposition date: 2014-10-21, release date: 2015-09-16, Last modification date: 2023-09-20)

Primary citation

Atigadda, V.R.,Xia, G.,Deshpande, A.,Wu, L.,Kedishvili, N.,Smith, C.D.,Krontiras, H.,Bland, K.I.,Grubbs, C.J.,Brouillette, W.J.,Muccio, D.D.
Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers.
J.Med.Chem., 58:7763-7774, 2015

PubMed Abstract: (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid (UAB30) is currently undergoing clinical evaluation as a novel cancer prevention agent. In efforts to develop even more highly potent rexinoids that prevent breast cancer without toxicity, we further explore here the structure-activity relationship of two separate classes of rexinoids. UAB30 belongs to the class II rexinoids and possesses a 9Z-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9Z-tetraenoic acid chain bonded to a disubstituted cyclohexenyl ring. Among the 12 class I and class II rexinoids evaluated, the class I rexinoid 11 is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid 11 also reduces the size of established tumors and exhibits a therapeutic effect. However, 11 induces hypertriglyceridemia at its effective dose. On the other hand rexinoid 10 does not increase triglyceride levels while being effective in the in vivo chemoprevention assay. X-ray studies of four rexinoids bound to the ligand binding domain of the retinoid X receptor reveal key structural aspects that enhance potency as well as those that enhance the synthesis of lipids.

PubMed: 26331194
DOI: 10.1021/acs.jmedchem.5b00829

Experimental method

X-RAY DIFFRACTION (2.7 Å)