4POH: Crystal Structure Of Human Retinoid X Receptor Alpha-ligand Binding Domain Complex With 8-methyl Uab30 And The Coactivator Peptide Grip-1

Citation:
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 hRXRalpha. 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 hRXRalpha-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
PDB ID: 4POHDownload
MMDB ID: 120854
PDB Deposition Date: 2014/2/25
Updated in MMDB: 2014/07
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 4POH: dimeric; determined by author and by software (PISA)
Molecular Components in 4POH
Label Count Molecule
Proteins (2 molecules)
1
Retinoic Acid Receptor Rxr-alpha(Gene symbol: RXRA)
Molecule annotation
1
Nuclear Receptor Coactivator 2(Gene symbol: NCOA2)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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