2ZY0

Crystal structure of the human RXR alpha ligand binding domain bound to a synthetic agonist compound and a coactivator peptide

Summary for 2ZY0

• Entry DOI: 10.2210/pdb2zy0/pdb
• Related: 1FBY 1MV9 1MVC 2ZXZ
• Descriptor: Retinoic acid receptor RXR-alpha, GRIP1 from Nuclear receptor coactivator 2, 4-[2-(1,1,3,3-tetramethyl-2,3-dihydro-1H-1,3-benzodisilol-5-yl)-1,3-dioxolan-2-yl]benzoic acid, ... (4 entities in total)
• Functional Keywords: transcription regulation, nuclear receptor, structural genomics, structural genomics consortium for research on gene expression, sgcges, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : P19793 Q15596
• Total number of polymer chains: 4
• Total formula weight: 57669.01

Authors

Sato, Y.,Antony, P.,Rochel, N.,Moras, D.,Structural Genomics Consortium for Research on Gene Expression (SGCGES) (deposition date: 2009-01-09, release date: 2009-08-11, Last modification date: 2023-11-01)

Primary citation

Lippert, W.P.,Burschka, C.,Gotz, K.,Kaupp, M.,Ivanova, D.,Gaudon, C.,Sato, Y.,Antony, P.,Rochel, N.,Moras, D.,Gronemeyer, H.,Tacke, R.
Silicon analogues of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology
Chemmedchem, 4:1143-1152, 2009

PubMed Abstract: C/Si switch: Twofold sila-substitution (C/Si exchange) in the RXR-selective retinoids 4 a (SR11237) and 5 a leads to 4 b (disila-SR11237) and 5 b, respectively. Chemistry and biology of the C/Si pairs are reported.SR11237 (BMS649, 4 a) is a pan-RXR-selective retinoid agonist. Its silicon analogue, disila-SR11237 (4 b; twofold C/Si exchange), was prepared in a multistep synthesis by starting from 1,2-bis(ethynyldimethylsilyl)ethane. In addition, the related C/Si analogues 5 a and 5 b, with an indane (disila-indane) instead of a tetraline (disila-tetraline) skeleton, were synthesized. The C/Si pairs 4 a/4 b and 5 a/5 b were studied for their interaction with retinoid receptors and were demonstrated to be highly potent RXR-selective ("rexinoid") agonists. Interestingly, twofold C/Si exchange in the indane moiety of 5 a resulted in a 10-fold increase in biological activity of the corresponding silicon-containing rexinoid 5 b, possibly resulting from an increased receptor affinity or a divergent allosteric effect on co-regulator-binding surfaces. The crystal structures of the ternary complexes formed by 5 a and 5 b, respectively, with the ligand-binding domain of hRXRalpha and a peptide of the co-activator TIF2/GRIP1 revealed additional interactions of the disila analogue 5 b with the H7 and H11 residues, supporting the first option of increased binding affinity. This is the first demonstration of an increase in binding affinity of a ligand to a nuclear receptor by C/Si replacement, thereby adding this C/Si switch strategy to the repertoire of nuclear receptor ligand design.

PubMed: 19496083
DOI: 10.1002/cmdc.200900090

Experimental method

X-RAY DIFFRACTION (2.9 Å)