Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Mutations within the Cholecystokinin-B/Gastrin Receptor Ligand ‘Pocket’ Interconvert the Functions of Nonpeptide Agonists and Antagonists

Michael Bläker, Yong Ren, Michelle C. Gordon, Jean E. Hsu, Martin Beinborn and Alan S. Kopin
Molecular Pharmacology November 1998, 54 (5) 857-863; DOI: https://doi.org/10.1124/mol.54.5.857
Michael Bläker
Division of Gastroenterology and GRASP Digestive Disease Center, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yong Ren
Division of Gastroenterology and GRASP Digestive Disease Center, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle C. Gordon
Division of Gastroenterology and GRASP Digestive Disease Center, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean E. Hsu
Division of Gastroenterology and GRASP Digestive Disease Center, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Beinborn
Division of Gastroenterology and GRASP Digestive Disease Center, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alan S. Kopin
Division of Gastroenterology and GRASP Digestive Disease Center, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

We have reported previously that the transmembrane domains of the cholecystokinin-B/gastrin receptor (CCK-BR) comprise a putative ligand binding pocket. In the present study, we examined whether amino acid substitutions within the CCK-BR pocket altered the affinities and/or functional activities of L-365,260 (the prototypical nonpeptide CCK-BR antagonist) and two structural derivatives, YM022 (a higher affinity antagonist) and L-740,093S (a partial agonist). Eight amino acids that project into the CCK-BR pocket were individually replaced by alanine, using site-directed mutagenesis. Affinities for the nonpeptide molecules, as well as ligand-induced inositol phosphate production, were assessed with the wild-type and mutant receptors. For each of the nonpeptide ligands examined, a distinct series of mutations altered the affinity, suggesting that each ligand possessed a characteristic pattern of interactions within the CCK-BR pocket. Basal signaling levels and inositol phosphate formation induced by the full agonist CCK octapeptide were comparable for the wild-type receptor and all of the mutant CCK-BR forms. In contrast to the peptide agonist CCK octapeptide, the functional activities of the nonpeptide molecules were selectively altered by single point mutations within the CCK-BR pocket, resulting in interconversion of agonists and antagonists. These findings suggest that interactions between nonpeptide molecules and transmembrane domain amino acids of the CCK-BR can determine the functional activity and affinity of the ligands.

Footnotes

    • Received January 20, 1998.
    • Accepted July 31, 1998.
  • Send reprint requests to: Alan S. Kopin, M.D., GRASP Digestive Disease Center, New England Medical Center, Box 239, 750 Washington St., Boston, MA 02111. E-mail:alan.kopin{at}es.nemc.org

  • This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant DK46767) and an American Digestive Health Foundation/American Gastroenterological Association Industry Research Scholar Award (M.Be.). M.Bl. is supported by the Deutsche Forschungsgemeinschaft.

  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Mutations within the Cholecystokinin-B/Gastrin Receptor Ligand ‘Pocket’ Interconvert the Functions of Nonpeptide Agonists and Antagonists
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Mutations within the Cholecystokinin-B/Gastrin Receptor Ligand ‘Pocket’ Interconvert the Functions of Nonpeptide Agonists and Antagonists

Michael Bläker, Yong Ren, Michelle C. Gordon, Jean E. Hsu, Martin Beinborn and Alan S. Kopin
Molecular Pharmacology November 1, 1998, 54 (5) 857-863; DOI: https://doi.org/10.1124/mol.54.5.857

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Mutations within the Cholecystokinin-B/Gastrin Receptor Ligand ‘Pocket’ Interconvert the Functions of Nonpeptide Agonists and Antagonists

Michael Bläker, Yong Ren, Michelle C. Gordon, Jean E. Hsu, Martin Beinborn and Alan S. Kopin
Molecular Pharmacology November 1, 1998, 54 (5) 857-863; DOI: https://doi.org/10.1124/mol.54.5.857
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Analgesic Effects and Mechanisms of Licochalcones
  • Induced Fit Ligand Binding to CYP3A4
  • Englerin A Inhibits T-Type Channels
Show more Article

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics