Evidence map›Paper›PMID 25319540›Full record

ArticleMolecular pharmacology2015

Development of a highly selective allosteric antagonist radioligand for the type 1 cholecystokinin receptor and elucidation of its molecular basis of binding.

Maoqing Dong, Ashton M Vattelana, Polo C-H Lam, Andrew J Orry, Ruben Abagyan, Arthur Christopoulos, Patrick M Sexton, David R Haines, Laurence J Miller

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
1.0field-weighted citation impact, top 24% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 11 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 1 institution in 2 countries.

Maoqing DongDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (M.D., L.J.M.); Department of Chemistry, Wellesley College, Wellesley, Massachusetts (A.M.V., D.R.H.); Molsoft LLC, La Jolla, California (P.C.-H.L., A.J.O., R.A.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California (R.A.); and Department of Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (A.C., P.M.S.).ORCID http://orcid.org/0000-0002-0775-6762
Ashton M VattelanaDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (M.D., L.J.M.); Department of Chemistry, Wellesley College, Wellesley, Massachusetts (A.M.V., D.R.H.); Molsoft LLC, La Jolla, California (P.C.-H.L., A.J.O., R.A.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California (R.A.); and Department of Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (A.C., P.M.S.).
Polo C-H LamDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (M.D., L.J.M.); Department of Chemistry, Wellesley College, Wellesley, Massachusetts (A.M.V., D.R.H.); Molsoft LLC, La Jolla, California (P.C.-H.L., A.J.O., R.A.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California (R.A.); and Department of Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (A.C., P.M.S.).
Andrew J OrryDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (M.D., L.J.M.); Department of Chemistry, Wellesley College, Wellesley, Massachusetts (A.M.V., D.R.H.); Molsoft LLC, La Jolla, California (P.C.-H.L., A.J.O., R.A.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California (R.A.); and Department of Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (A.C., P.M.S.).
Ruben AbagyanDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (M.D., L.J.M.); Department of Chemistry, Wellesley College, Wellesley, Massachusetts (A.M.V., D.R.H.); Molsoft LLC, La Jolla, California (P.C.-H.L., A.J.O., R.A.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California (R.A.); and Department of Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (A.C., P.M.S.).
Arthur ChristopoulosDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (M.D., L.J.M.); Department of Chemistry, Wellesley College, Wellesley, Massachusetts (A.M.V., D.R.H.); Molsoft LLC, La Jolla, California (P.C.-H.L., A.J.O., R.A.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California (R.A.); and Department of Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (A.C., P.M.S.).
Patrick M SextonDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (M.D., L.J.M.); Department of Chemistry, Wellesley College, Wellesley, Massachusetts (A.M.V., D.R.H.); Molsoft LLC, La Jolla, California (P.C.-H.L., A.J.O., R.A.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California (R.A.); and Department of Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (A.C., P.M.S.).ORCID http://orcid.org/0000-0001-8902-2473
David R HainesDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (M.D., L.J.M.); Department of Chemistry, Wellesley College, Wellesley, Massachusetts (A.M.V., D.R.H.); Molsoft LLC, La Jolla, California (P.C.-H.L., A.J.O., R.A.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California (R.A.); and Department of Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (A.C., P.M.S.).
Laurence J MillerDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (M.D., L.J.M.); Department of Chemistry, Wellesley College, Wellesley, Massachusetts (A.M.V., D.R.H.); Molsoft LLC, La Jolla, California (P.C.-H.L., A.J.O., R.A.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California (R.A.); and Department of Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (A.C., P.M.S.) miller@mayo.edu.
Wellesley College · US

Funding

Type A CCK Receptor Structure, Function and RegulationR37DK032878 · NIDDK · MAYO CLINIC COLL OF MED, MAYO CLINIC AZ · PI MILLER, LAURENCE J · 2001 to 2010
$4.5M
Macromolecular DockingR01GM071872 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ABAGYAN, RUBEN · 2004 to 2017
$4.2M
Type A CCK Receptor Structure, Function & RegulationR01DK032878 · NIDDK · MAYO CLINIC COLL OF MEDICINE, ROCHESTER · PI MILLER, LAURENCE J · 1986 to 2014
$2.5M
NIDDK NIH HHS DK032878NIDDK NIH HHS R01 DK032878NIDDK NIH HHS R37 DK032878NIGMS NIH HHS R01 GM071872
6 · The paper itself

Abstract

Understanding the molecular basis of ligand binding to receptors provides insights useful for rational drug design. This work describes development of a new antagonist radioligand of the type 1 cholecystokinin receptor (CCK1R), (2-fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinylcarbonyl)amino]-6-methoxy-2-oxo-l-H-indole-3-propanoate (T-0632), and exploration of the molecular basis of its binding. This radioligand bound specifically with high affinity within an allosteric pocket of CCK1R. T-0632 fully inhibited binding and action of CCK at this receptor, while exhibiting no saturable binding to the closely related type 2 cholecystokinin receptor (CCK2R). Chimeric CCK1R/CCK2R constructs were used to explore the molecular basis of T-0632 binding. Exchanging exonic regions revealed the functional importance of CCK1R exon 3, extending from the bottom of transmembrane segment (TM) 3 to the top of TM5, including portions of the intramembranous pocket as well as the second extracellular loop region (ECL2). However, CCK1R mutants in which each residue facing the pocket was changed to that present in CCK2R had no negative impact on T-0632 binding. Extending the chimeric approach to ECL2 established the importance of its C-terminal region, and site-directed mutagenesis of each nonconserved residue in this region revealed the importance of Ser(208) at the top of TM5. A molecular model of T-0632-occupied CCK1R was consistent with these experimental determinants, also identifying Met(121) in TM3 and Arg(336) in TM6 as important. Although these residues are conserved in CCK2R, mutating them had a distinct impact on the two closely related receptors, suggesting differential orientation. This establishes the molecular basis of binding of a highly selective nonpeptidyl allosteric antagonist of CCK1R, illustrating differences in docking that extend beyond determinants attributable to distinct residues lining the intramembranous pocket in the two receptor subtypes.

Indexed as

Amino AcidsAnimalsBinding SitesChlorocebus aethiopsCHO CellsCOS CellsCricetulusHumansIndolesMolecular Docking SimulationMutagenesis, Site-DirectedRadioligand AssayReceptor, Cholecystokinin AReceptor, Cholecystokinin BAmino AcidsIndolesReceptor, Cholecystokinin AReceptor, Cholecystokinin BT 0632

Identifiers

PMID25319540
PMCPMC4279081
OpenAlexW2105102294

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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.