1RDT

Crystal Structure of a new rexinoid bound to the RXRalpha ligand binding doamin in the RXRalpha/PPARgamma heterodimer

Summary for 1RDT

• Entry DOI: 10.2210/pdb1rdt/pdb
• Related: 1FM6 1FM9
• Descriptor: Retinoic acid receptor RXR-alpha, LxxLL motif coactivator, Peroxisome proliferator activated receptor gamma, ... (7 entities in total)
• Functional Keywords: hormone, receptor, polymorphism, hormone-growth factor complex, hormone/growth factor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P19793 P37231
• Total number of polymer chains: 4
• Total formula weight: 65772.21

Authors

Haffner, C.D.,Lenhard, J.M.,Miller, A.B.,McDougald, D.L.,Dwornik, K.,Ittoop, O.R.,Gampe Jr., R.T.,Xu, H.E.,Blanchard, S.,Montana, V.G. (deposition date: 2003-11-06, release date: 2004-11-09, Last modification date: 2023-08-23)

Primary citation

Haffner, C.D.,Lenhard, J.M.,Miller, A.B.,McDougald, D.L.,Dwornik, K.,Ittoop, O.R.,Gampe Jr., R.T.,Xu, H.E.,Blanchard, S.,Montana, V.G.,Consler, T.G.,Bledsoe, R.K.,Ayscue, A.,Croom, D.
Structure-based design of potent retinoid X receptor alpha agonists.
J.Med.Chem., 47:2010-2029, 2004

PubMed Abstract: A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.

PubMed: 15056000
DOI: 10.1021/jm030565g

Experimental method

X-RAY DIFFRACTION (2.4 Å)