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Intermolecular Interactions between Cholecystokinin-8 and the Third Extracellular Loop of the Cholecystokinin-2 Receptor†,‡

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Departments of Chemistry and Molecular Pharmacology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912
Cite this: Biochemistry 2002, 41, 14, 4560–4566
Publication Date (Web):March 15, 2002
https://doi.org/10.1021/bi0160009
Copyright © 2002 American Chemical Society
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    Abstract

    The structure of the third extracellular loop of the human cholecystokinin-2 receptor, CCK2-R(352−379), and its interactions with the C-terminal octapeptide of cholecystokinin (CCK-8) have been determined by high-resolution NMR and computer simulations. In the presence of dodecylphosphocholine micelles, the structure of the receptor fragment consisted of three helices, with the first and third corresponding to residues of the extracellular ends of transmembrane helices (TM) 6 and 7, respectively. The central, extracellular helix, consisting of residues 363−368, was found to be closely associated with the membrane mimetic used during the spectroscopic studies and molecular dynamics (MD) simulations. Upon titration of CCK-8 to the receptor domain, chemical shift perturbation and intermolecular NOEs (Trp30, Met31 of CCK-8 and P371, F374 of CCK2-R) indicated the formation of a stable complex and specific ligand/receptor interactions. Using the NOE-generated intermolecular contact points, extensive MD simulations of CCK-8 bound to the CCK2 receptor were carried out. The results, with CCK-8 in close proximity to TM7, differ from previous structural studies of CCK-8 association with CCK1-R, in which the ligand formed a number of interactions with TM6. These differences may play a role in the ligand specificity displayed by the CCK1 and CCK2 receptor subtypes.

    †

     This work was supported by the Research Foundation through a Cottrell Scholars Award (D.F.M.) and a Henry and Camille Dreyfus Scholars and Teachers Award (D.F.M.).

    ‡

     The structure coordinates have been deposited in the Brookhaven Protein Data Bank (filename 1L4T).

    §

     Department of Chemistry.

    *

     To whom correspondence should be addressed at the Department of Molecular Pharmacology. Phone:  (401) 863-2139. Fax:  (401) 863-1595. E-mail:  [email protected].

    ‖

     Department of Molecular Pharmacology.

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