PDBsum entry 4poj

Transcription

PDB id: 4poj

Contents

Protein chains

214 a.a.

11 a.a.

Ligands

2VP

Waters ×135

PDB id:

4poj

Name:

Transcription

Title:

Crystal structure of human retinoid x receptor alpha-ligand binding domain complex with 7-methyl uab30 and the coactivator peptide grip-1

Structure:

Retinoic acid receptor rxr-alpha. Chain: a. Fragment: ligand binding domain, unp residues 228-458. Synonym: nuclear receptor subfamily 2 group b member 1, retinoid x receptor alpha. Engineered: yes. Nuclear receptor coactivator 2. Chain: b. Fragment: coactivator peptide, unp residues 686-698.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Strain: p19793. Gene: nr2b1, rxra, rxra nr2b1. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.00Å R-factor: 0.218 R-free: 0.261

Authors:

G.Xia,C.D.Smith,D.D.Muccio

Key ref:

V.R.Atigadda et al. (2014). Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity. J Med Chem, 57, 5370-5380. PubMed id: 24801499 DOI: 10.1021/jm5004792

Date:

25-Feb-14 Release date: 18-Jun-14

Protein chain

P19793  (RXRA_HUMAN) -  Retinoic acid receptor RXR-alpha from Homo sapiens

Seq: 462 a.a.

Struc: 214 a.a.

Protein chain

Q15596  (NCOA2_HUMAN) -  Nuclear receptor coactivator 2 from Homo sapiens

Seq: 1464 a.a.

Struc: 11 a.a.

DOI no: 10.1021/jm5004792

J Med Chem 57:5370-5380 (2014)

PubMed id: 24801499

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

V.R.Atigadda, G.Xia, A.Desphande, L.J.Boerma, S.Lobo-Ruppert, C.J.Grubbs, C.D.Smith, W.J.Brouillette, D.D.Muccio.

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.