J. Biol. Chem., Vol. 268, Issue 4, 2319-2323, 02, 1993
Molecular basis for the species selectivity of the substance P antagonist CP-96,345
BS Sachais, RM Snider, JA Lowe 3d and JE Krause
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110.
The non-peptide substance P (SP) antagonist CP-96,345 has a 90-fold
selectivity for the human neurokinin-1 (NK-1) or SP receptor over the rat
NK-1 receptor, while the agonist SP shows no such selectivity. The cloned
NK-1 receptors from these two species have primary protein structures that
differ in only 22 of 407 residues. Wild type, chimeric, and point-mutated
NK-1 receptors have been created and functionally expressed to understand
the structural basis of this species selectivity. Residue 290 in the
seventh putative membrane-spanning region is responsible for 20-fold of the
affinity difference seen for CP-96,345 between the rat and human NK-1
receptors. Residues in the second extracellular loop and in
membrane-spanning region six contribute the additional 3-5-fold of the
species difference. The direct or indirect action of these residues with
this nonpeptidic antagonist is discussed. This study serves to emphasize
the need for species-appropriate in vitro models for the screening of
antagonists in the search for therapeutics, and provides useful information
to model nonpeptidic antagonist interactions with peptide hormone
receptors.
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