PDBsum entry 4m8h

Transcription

PDB id: 4m8h

Contents

Protein chains

214 a.a.

11 a.a.

Ligands

R4M

Waters ×129

PDB id:

4m8h

Name:

Transcription

Title:

Crystal structure of human retinoid x receptor alpha-ligand binding domain complex with (r)4-methyl 9cuab30 and coactivator peptide grip- 1

Structure:

Retinoic acid receptor rxr-alpha. Chain: a. Fragment: hrxralpha-lbd, 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: grip-1, unp residues 686-696.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Strain: p19793. Gene: nr2b1, rxra. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Other_details: grip-1 from anaspec. Inc

Resolution:

2.20Å R-factor: 0.228 R-free: 0.265

Authors:

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

Key ref:

A.Desphande et al. (2014). Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention. Bioorg Med Chem Lett, 22, 178-185. PubMed id: 24359708 DOI: 10.1016/j.bmc.2013.11.039

Date:

13-Aug-13 Release date: 22-Jan-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: 10.1016/j.bmc.2013.11.039

Bioorg Med Chem Lett 22:178-185 (2014)

PubMed id: 24359708

Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.

A.Desphande, G.Xia, L.J.Boerma, K.K.Vines, V.R.Atigadda, S.Lobo-Ruppert, C.J.Grubbs, F.L.Moeinpour, C.D.Smith, K.Christov, 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, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.