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Papers In Press, published online ahead of print September 23, 2003
Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS, Gif-sur-Yvette 91198
Corresponding Author: ruat{at}nbcm.cnrs-gif.fr
A model of the calcium sensing receptor (CaSR) seven transmembrane domains was constructed based on the crystal structure of bovine rhodopsin. This model was used for docking (1S,2S,1'R)-N1-(4-chlorobenzoyl)-N2-[1-(1-naphthyl)ethyl]-1,2-diaminocyclohexane (Calex 231), a novel potent negative allosteric modulator which blocks (IC50 of 0.39 µM) increases of [3H]inositol phosphates elicited by activating the human wild type CaSR transiently expressed in HEK293 cells. In this model, E8377.39 plays a pivotal role in anchoring the two nitrogen atoms of Calex 231 and locating the aromatic moieties in two adjacent hydrophobic pockets delineated by transmembrane domains 3, 5 and 6, and transmembrane domains 1, 2, 3 and 7, respectively. To demonstrate its validity, we have mutated selected residues and analyzed biochemical and pharmacological properties of the mutated receptors transfected in HEK293 cells. Two receptor mutations, F684A3.32 and E837A7.39, caused a loss of Calex 231's ability to inhibit Ca2+-induced accumulation of [3H]inositol phosphates. Three other mutations, F688A3.36, W818A6.48, and I841A7.43, produced a marked increase of the IC50 of Calex 231 for the Ca2+ response whereas L776A5.42 and F821A6.51 mutations led to a decrease of the IC50. Our data validate the proposed model for the allosteric interaction of Calex 231 with the seven transmembrane domains of the CaSR. Interestingly, the residues at the same positions have been shown to delimit the antagonist-binding cavity of many diverse GPCRs. Our present study furthermore suggests that the crystal structure of bovine rhodopsin exhibits sufficient mimicry with the ground state of a very divergent class 3 receptor to predict the interaction of antagonists with the heptahelical bundle of diverse GP
J. Biol. Chem, 10.1074/jbc.M308010200
Submitted on July 23, 2003
Revised on September 22, 2003
Accepted on September 23, 2003
Modeling and mutagenesis of the binding site of Calex 231, a novel negative allosteric modulator of the extracellular Ca2+ sensing receptor
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