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Improved model building and assessment of the Calcium‐sensing receptor transmembrane domain
Author(s) -
Bu Lintao,
Michino Mayako,
Wolf Romain M.,
Brooks Charles L.
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21685
Subject(s) - rhodopsin , docking (animal) , transmembrane domain , allosteric regulation , moiety , g protein coupled receptor , homology modeling , chemistry , biophysics , stereochemistry , crystallography , biochemistry , receptor , biology , retinal , medicine , nursing , enzyme
A three‐dimensional model of the human Calcium‐sensing receptor (CaSR) seven transmembrane domain was built via a novel sequence alignment method based on the conserved contacts in proteins using the crystal structure of bovine rhodopsin as the template. This model was tested by docking NPS 2143, the first identified allosteric antagonist of CaSR. In our model, Glu837 plays a critical role in anchoring the protonated nitrogen atom and hydroxy oxygen atom of NPS 2143. The phenyl moiety of the ligand contacts residues Phe668, Pro672, and Ile841. The naphthalene moiety is surrounded by several hydrophobic residues, including Phe684, Phe688, and Phe821. Our model appears to be consistent with all six residues that have been demonstrated to be critical for NPS 2143 binding, in contrast with existing homology models based on traditional sequence alignment of CaSR to rhodopsin. This provides validation of our sequence alignment method and the use of the rhodopsin backbone as the initial structure in homology modeling of other G protein‐coupled receptors that are not members of the rhodopsin family. Proteins 2008. © 2007 Wiley‐Liss, Inc.