PDBsum entry 4rmc

Transcription

PDB id: 4rmc

Contents

Protein chains

214 a.a.

11 a.a.

Ligands

3SV

Waters ×130

PDB id:

4rmc

Name:

Transcription

Title:

Crystal structure of human retinoid x receptor alpha-ligand binding domain complex with 9cuab76 and the coactivator peptide grip-1

Structure:

Retinoic acid receptor rxr-alpha. Chain: a. Fragment: ligand binding domain 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 residues 686-698.

Source:

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

Resolution:

2.70Å R-factor: 0.187 R-free: 0.265

Authors:

G.Xia,D.D.Muccio

Key ref:

V.R.Atigadda et al. (2015). Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers. J Med Chem, 58, 7763-7774. PubMed id: 26331194 DOI: 10.1021/acs.jmedchem.5b00829

Date:

21-Oct-14 Release date: 16-Sep-15

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/acs.jmedchem.5b00829

J Med Chem 58:7763-7774 (2015)

PubMed id: 26331194

Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers.

V.R.Atigadda, G.Xia, A.Deshpande, L.Wu, N.Kedishvili, C.D.Smith, H.Krontiras, K.I.Bland, C.J.Grubbs, W.J.Brouillette, D.D.Muccio.

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.