ArticleThe Journal of biological chemistry2014
A type 1 cholecystokinin receptor mutant that mimics the dysfunction observed for wild type receptor in a high cholesterol environment.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 24 citations in OpenAlex.
- Effects of Membrane Cholesterol on the Structure and Function of Selected Class A GPCRs─Challenges and Future Perspectives.Biochemistry · 2025Review
- Cholesterol residence time drives regulation of the G protein-coupled cholecystokinin receptor.Molecular pharmacology · 2025Article
- Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling.PLoS biology · 2024Article
- Article
- Evidence that specific interactions play a role in the cholesterol sensitivity of G protein-coupled receptors.Biochimica et biophysica acta. Biomembranes · 2021Article
- Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins provide insight into mechanisms of G protein selectivity.PLoS biology · 2021Article
- Roles of Cholecystokinin in the Nutritional Continuum. Physiology and Potential Therapeutics.Frontiers in endocrinology · 2021Review
- Discovery of a Positive Allosteric Modulator of Cholecystokinin Action at CCK1R in Normal and Elevated Cholesterol.Frontiers in endocrinology · 2021Article
- Functional marriage in plasma membrane: Critical cholesterol level-optimal protein activity.British journal of pharmacology · 2020Review
- Changes in the plasma membrane in metabolic disease: impact of the membrane environment on G protein-coupled receptor structure and function.British journal of pharmacology · 2018Review
- Permanent Photodynamic Cholecystokinin 1 Receptor Activation: Dimer-to-Monomer Conversion.Cellular and molecular neurobiology · 2018Article
- Cholecystokinin responsiveness varies across the population dependent on metabolic phenotype.The American journal of clinical nutrition · 2017Article
- Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor.International journal of obesity supplements · 2016Review
- Biased μ-opioid receptor agonists diversely regulate lateral mobility and functional coupling of the receptor to its cognate G proteins.Naunyn-Schmiedeberg's archives of pharmacology · 2016Article
- Beneficial effects of β-sitosterol on type 1 cholecystokinin receptor dysfunction induced by elevated membrane cholesterol.Clinical nutrition (Edinburgh, Scotland) · 2016Article
- Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target.Trends in endocrinology and metabolism: TEM · 2016Review
- Molecular Mechanism of Action of Triazolobenzodiazepinone Agonists of the Type 1 Cholecystokinin Receptor. Possible Cooperativity across the Receptor Homodimeric Complex.Journal of medicinal chemistry · 2015Article
- Impact of ursodeoxycholic acid on a CCK1R cholesterol-binding site may contribute to its positive effects in digestive function.American journal of physiology. Gastrointestinal and liver physiology · 2015Article
- Elimination of a cholecystokinin receptor agonist 'trigger' in an effort to develop positive allosteric modulators without intrinsic agonist activity.Bioorganic & medicinal chemistry letters · 2015Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Cholecystokinin (CCK) stimulates the type 1 CCK receptor (CCK1R) to elicit satiety after a meal. Agonists with this activity, although potentially useful for treatment of obesity, can also have side effects and toxicities of concern, making the development of an intrinsically inactive positive allosteric modulator quite attractive. Positive allosteric modulators also have the potential to correct the defective receptor-G protein coupling observed in the high membrane cholesterol environment described in metabolic syndrome. Current model systems to study CCK1R in such an environment are unstable and expensive to maintain. We now report that the Y140A mutation within a cholesterol-binding motif and the conserved, class A G protein-coupled receptor-specific (E/D)RY signature sequence results in ligand binding and activity characteristics similar to wild type CCK1R in a high cholesterol environment. This is true for natural CCK, as well as ligands with distinct chemistries and activity profiles. Additionally, the Y140A construct also behaved like CCK1R in high cholesterol in regard to its internalization, sensitivity to a nonhydrolyzable GTP analog, and anisotropy of a bound fluorescent CCK analog. Chimeric CCK1R/CCK2R constructs that systematically changed the residues in the allosteric ligand-binding pocket were studied in the presence of Y140A. This established increased importance of unique residues within TM3 and reduced the importance of TM2 for binding in the presence of this mutation, with the agonist trigger likely pulled away from its Leu(356) target on TM7. The distinct conformation of this intramembranous pocket within Y140A CCK1R provides an opportunity to normalize this by using a small molecule allosteric ligand, thereby providing safe and effective correction of the coupling defect in metabolic syndrome.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.