4POH

Crystal structure of human Retinoid X Receptor alpha-ligand binding domain complex with 8-methyl UAB30 and the coactivator peptide GRIP-1

Summary for 4POH

• Entry DOI: 10.2210/pdb4poh/pdb
• Related: 3OAP 4K4J 4POJ
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, (2E,4E,6Z,8E)-3,7-dimethyl-8-(8-methyl-3,4-dihydronaphthalen-1(2H)-ylidene)octa-2,4,6-trienoic acid, ... (4 entities in total)
• Functional Keywords: ligand binding domain, nuclear receptor, cancer, methyl substituted rexinoid, 8-methyl uab30, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P19793 Q15596
• Total number of polymer chains: 2
• Total formula weight: 27785.30

Authors

Xia, G.,Smith, C.D.,Muccio, D.D. (deposition date: 2014-02-25, release date: 2014-06-18, Last modification date: 2023-09-20)

Primary citation

Atigadda, V.R.,Xia, G.,Desphande, A.,Boerma, L.J.,Lobo-Ruppert, S.,Grubbs, C.J.,Smith, C.D.,Brouillette, W.J.,Muccio, D.D.
Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
J.Med.Chem., 57:5370-5380, 2014

PubMed Abstract: (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.

PubMed: 24801499
DOI: 10.1021/jm5004792

Experimental method

X-RAY DIFFRACTION (2.3 Å)