Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Harikumar, Kaleeckal G.; Cawston, Erin E.; Lam, Polo C.‐H.; Patil, Achyut; Orry, Andrew; Henke, Brad R.; Abagyan, Ruben; Christopoulos, Arthur; Sexton, Patrick M.; Miller, Laurence J.

doi:10.1074/jbc.m113.480715

Cited by 21 publications

(76 citation statements)

References 31 publications

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“…40 It was also confirmed using fluorescence quenching of ligand binding 41 and the impact of receptor mutagenesis on ligand binding. 42,43 The allosteric nature of this small-molecule-binding site was further confirmed using pharmacologic analyses, including the kinetics of ligand dissociation and the impact of orthosteric and possible allosteric ligands on the functions of each other. [42][43][44] Radioiodinated small-molecule CCK1R ligands have been developed 45,46 that provide a means for direct displacement from this allosteric pocket to establish the molecular basis for the binding of small-molecule ligands.…”

Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 88%

“…20 Once again, this model had great predictive power, being able to effectively distinguish CCK1R agonists from CCK1R antagonists. 43 This has provided clear evidence of the differences in the shape of this pocket when in inactive and active conformations.…”

Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 93%

“…This effort included not only the docking of a single benzodiazepine antagonist ligand, but also a ligand-guided computational approach using many molecules that have been reported and that reside in public databases to gain more general understanding of this pocket. 42,43 This molecular model has substantial predictive power, with the model being able to distinguish ligands of this receptor from those of other receptors, and it was even able to very effectively distinguish ligands binding to the CCK1R from those binding to the very closely related type 2 CCK receptor (CCK2R).…”

Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 99%

“…47 This, too, was used in a ligand-directed computational effort to generalize our understanding of the active conformation of this pocket. 43 It also provided molecular insights into the determinants of biological activity, with evidence for a key interaction between a 'trigger functionality' within a benzodiazepine agonist and the receptor residues it likely interacts with. 20 Once again, this model had great predictive power, being able to effectively distinguish CCK1R agonists from CCK1R antagonists.…”

Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 99%

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Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

et al. 2016

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The gastrointestinal (GI) tract has a central role in nutritional homeostasis, as location for food ingestion, digestion and absorption, with the gut endocrine system responding to and regulating these events, as well as influencing appetite. One key GI hormone with the full spectrum of these activities is cholecystokinin (CCK), a peptide released from neuroendocrine I cells scattered through the proximal intestine in response to fat and protein, with effects to stimulate gall bladder contraction and pancreatic exocrine secretion, to regulate gastric emptying and intestinal transit, and to induce satiety. There has been interest in targeting the type 1 CCK receptor (CCK1R) for drug development to provide non-caloric satiation as an aid to dieting and weight loss; however, there have been concerns about CCK1R agonists related to side effects and potential trophic impact on the pancreas. A positive allosteric modulator (PAM) of CCK action at this receptor without intrinsic agonist activity could provide a safer and more effective approach to long-term administration. In addition, CCK1R stimulus-activity coupling has been shown to be negatively affected by excess membrane cholesterol, a condition described in the metabolic syndrome, thereby potentially interfering with an important servomechanism regulating appetite. A PAM targeting this receptor could also potentially correct the negative impact of cholesterol on CCK1R function. We will review the molecular basis for binding natural peptide agonist, binding and action of small molecules within the allosteric pocket, and the impact of cholesterol. Novel strategies for taking advantage of this receptor for the prevention and management of obesity will be reviewed.International Journal of Obesity Supplements (2016) 6, S22-S27; doi:10.1038/ijosup.2016.5 INTRODUCTIONThe prevalence of obesity has been progressively increasing throughout the United States and around the world, contributing to a parallel increase in the prevalence of type 2 diabetes mellitus and its associated comorbidities. 1 These problems have been responsible for extraordinary morbidity, suffering, loss in productivity and premature mortality. In spite of major efforts to develop effective weight reduction diets, diet aids, medications, medical devices and surgical procedures, the trajectory for this continues in the wrong direction. Bariatric surgery has proven to be quite effective in patients with morbid obesity; 2 however, this is quite expensive and not scalable, certainly not keeping up with the increasing prevalence of the most severe end of this clinical continuum. The activity of acute dieting and exercise has been similarly effective in inducing weight loss; however, it has not been durable, with an extremely high incidence of regaining weight to or even beyond the starting point. After a long hiatus in approved drugs, three new diet medications have recently been approved, 3-5 but all carry concerns about safety, and there are requirements for registration and careful clinical follow-up, re...

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Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 88%

Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 93%

Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 99%

Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 99%

See 2 more Smart Citations

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

et al. 2016

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“…An understanding of the varied residues lining the small molecule-binding pocket high in the helical bundle of these receptors has provided a useful starting point for understanding the size and chemical characteristics of potential ligands. It has also become possible to extend these insights computationally, particularly when a series of ligands can be used to guide such refinement (Cawston et al, 2012;Harikumar et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Development of a Highly Selective Allosteric Antagonist Radioligand for the Type 1 Cholecystokinin Receptor and Elucidation of Its Molecular Basis of Binding

Dong

Vattelana

Lam

et al. 2015

Molecular Pharmacology

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Cholecystokinin (CCK) Regulation of Pancreatic Acinar Cells: Physiological Actions and Signal Transduction Mechanisms

Williams

2019

Comprehensive Physiology

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Pancreatic acinar cells synthesize and secrete about 20 digestive enzymes and ancillary proteins with the processes that match the supply of these enzymes to their need in digestion being regulated by a number of hormones (CCK, secretin and insulin), neurotransmitters (acetylcholine and VIP) and growth factors (EGF and IGF). Of these regulators, one of the most important and best studied is the gastrointestinal hormone, cholecystokinin (CCK). Furthermore, the acinar cell has become a model for seven transmembrane, heterotrimeric G protein coupled receptors to regulate multiple processes by distinct signal transduction cascades. In this review, we briefly describe the chemistry and physiology of CCK and then consider the major physiological effects of CCK on pancreatic acinar cells. The majority of the review is devoted to the physiologic signaling pathways activated by CCK receptors and heterotrimeric G proteins and the functions they affect. The pathways covered include the traditional second messenger pathways PLC‐IP3‐Ca 2+ , DAG‐PKC, and AC‐cAMP‐PKA/EPAC that primarily relate to secretion. Then there are the protein‐protein interaction pathways Akt‐mTOR‐S6K, the three major MAPK pathways (ERK, JNK, and p38 MAPK), and Ca 2+ ‐calcineurin‐NFAT pathways that primarily regulate non‐secretory processes including biosynthesis and growth, and several miscellaneous pathways that include the Rho family small G proteins, PKD, FAK, and Src that may regulate both secretory and nonsecretory processes but are not as well understood. © 2019 American Physiological Society. Compr Physiol 9:535‐564, 2019.

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Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Cited by 21 publications

References 31 publications

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

Development of a Highly Selective Allosteric Antagonist Radioligand for the Type 1 Cholecystokinin Receptor and Elucidation of Its Molecular Basis of Binding

Cholecystokinin (CCK) Regulation of Pancreatic Acinar Cells: Physiological Actions and Signal Transduction Mechanisms

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