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Vol. 58, Issue 1, 217-225, July 2000
Departments of Central Nervous System and Cardiovascular
Research (D.M., X.Y., C.D.S., M.P.G.), Bioinformatics (N.M.), and
Structural Chemistry (R.Z., J.P.D.), Schering-Plough Research
Institute, Kenilworth, New Jersey
A molecular model of the human melanin-concentrating hormone (MCH)
peptide was constructed and docked into a helical,
bacteriorhodopsin-based model of the recently identified human MCH
receptor. From this hormone-receptor complex, potential sites of
agonist-receptor interaction were identified, and site-directed
mutagenesis was used to substitute residues predicted to reside within
the receptor binding pocket. Substitution of Asp123(3.32)
in the third transmembrane domain of the receptor resulted in a loss of
detectable 125I-MCH binding and of MCH-stimulated
Ca2+ flux; cell surface expression of the mutant receptor
was not affected. Arg11 and Arg14 of the MCH
ligand were identified as potential sites of interaction with
Asp123(3.32). [Ala14]-MCH was equipotent to
native MCH in its ability to bind to and activate the wild-type MCH
receptor, whereas [Ala11]-MCH displayed a 3000-fold
reduction in binding affinity and a complete loss of measurable
functional activity. Furthermore, [Lys11]-MCH and
[D-Arg11]-MCH displayed reduced affinity for
the receptor. [Lys11]-MCH was observed to be a partial
agonist, eliciting approximately 67% of the native peptide's activity
in a Ca2+ flux assay, and
[D-Arg11]-MCH was determined to be a
functional antagonist with a Kb valve of
15.8 µM. These data provide evidence that a basic moiety with specific stereochemical requirements at this site is needed for receptor activation. We conclude that both Asp123(3.32) in
the MCH receptor and Arg11 in the MCH peptide are required
for the formation of the MCH peptide/receptor complex and propose that
they form a direct interaction that is critical for receptor function.
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