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Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.

Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD - J. Med. Chem. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of †Chemistry, ‡Biochemistry and Molecular Genetics, §Medicine, and ∥Vision Sciences, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.

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.

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Overlayof X-ray crystal structures of hRXRα-LBD bound to9cUAB30 (green), 1 (yellow), 2 (blue), 3 (magenta), and 4 (cyan). The coactivator peptideGRIP-1 is displayed in red, and the ligand binding pocket of hRXRα-LBDis highlighted in brown-gray mesh.
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fig2: Overlayof X-ray crystal structures of hRXRα-LBD bound to9cUAB30 (green), 1 (yellow), 2 (blue), 3 (magenta), and 4 (cyan). The coactivator peptideGRIP-1 is displayed in red, and the ligand binding pocket of hRXRα-LBDis highlighted in brown-gray mesh.

Mentions: The 3D fold of the hRXRα-LBD homodimer was nearly identicalregardless which 9cUAB30 homologue was bound. The backbone atoms ofeach structure were overlaid with the structure of hRXRα-LBDbound to 9cUAB30 and GRIP-1 complex (4K4J). The rmsd values for this overlay of229 backbone residues were 0.130, 0.139, 0.105, and 0.128 for homodimersbound to 1, 2, 3, and 4, respectively (Figure 2). We establishedthat four conformational changes occur in the layer between the rexinoidbinding site and the coactivator binding site.7,8 Eachof these conformational changes was present in the structures containingthe methyl homologues studied here. These allow helix 12 of the hRXRα-LBDto form the coactivator binding site. Together with helices 3 and4 residues, the ILxxLL motif of GRIP-1 bound to the hydrophobic pocketon the surface of the receptor and GRIP-1 was held by charge clamps.These interactions were identical for the structures reported hereand those reported previously.7 The onlyexception occurred when rexinoid 2 was bound. In thisstructure, the side chain of E456 (helix 12) extended completely intothe solvent and the charge clamp was not formed with H687 on GRIP-1.


Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.

Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD - J. Med. Chem. (2014)

Overlayof X-ray crystal structures of hRXRα-LBD bound to9cUAB30 (green), 1 (yellow), 2 (blue), 3 (magenta), and 4 (cyan). The coactivator peptideGRIP-1 is displayed in red, and the ligand binding pocket of hRXRα-LBDis highlighted in brown-gray mesh.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216212&req=5

fig2: Overlayof X-ray crystal structures of hRXRα-LBD bound to9cUAB30 (green), 1 (yellow), 2 (blue), 3 (magenta), and 4 (cyan). The coactivator peptideGRIP-1 is displayed in red, and the ligand binding pocket of hRXRα-LBDis highlighted in brown-gray mesh.
Mentions: The 3D fold of the hRXRα-LBD homodimer was nearly identicalregardless which 9cUAB30 homologue was bound. The backbone atoms ofeach structure were overlaid with the structure of hRXRα-LBDbound to 9cUAB30 and GRIP-1 complex (4K4J). The rmsd values for this overlay of229 backbone residues were 0.130, 0.139, 0.105, and 0.128 for homodimersbound to 1, 2, 3, and 4, respectively (Figure 2). We establishedthat four conformational changes occur in the layer between the rexinoidbinding site and the coactivator binding site.7,8 Eachof these conformational changes was present in the structures containingthe methyl homologues studied here. These allow helix 12 of the hRXRα-LBDto form the coactivator binding site. Together with helices 3 and4 residues, the ILxxLL motif of GRIP-1 bound to the hydrophobic pocketon the surface of the receptor and GRIP-1 was held by charge clamps.These interactions were identical for the structures reported hereand those reported previously.7 The onlyexception occurred when rexinoid 2 was bound. In thisstructure, the side chain of E456 (helix 12) extended completely intothe solvent and the charge clamp was not formed with H687 on GRIP-1.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of †Chemistry, ‡Biochemistry and Molecular Genetics, §Medicine, and ∥Vision Sciences, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.

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.

Show MeSH
Related in: MedlinePlus