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  1. Article ; Online: Allostery of atypical modulators at oligomeric G protein-coupled receptors.

    Shivnaraine, Rabindra V / Kelly, Brendan / Elmslie, Gwendolynne / Huang, Xi-Ping / Dong, Yue John / Seidenberg, Margaret / Wells, James W / Ellis, John

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 9265

    Abstract: Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the ... ...

    Abstract Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the M
    MeSH term(s) Allosteric Regulation ; Allosteric Site ; Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Ligands ; Molecular Dynamics Simulation ; Receptor, Muscarinic M2/chemistry ; Receptor, Muscarinic M2/genetics ; Receptor, Muscarinic M2/metabolism ; Tacrine/pharmacology
    Chemical Substances Ligands ; Receptor, Muscarinic M2 ; Tacrine (4VX7YNB537)
    Language English
    Publishing date 2021-04-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-88399-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Heterotropic Cooperativity within and between Protomers of an Oligomeric M2 Muscarinic Receptor

    Shivnaraine, Rabindra V / Huang Xi-Ping / Seidenberg Margaret / Ellis John / Wells James W

    Biochemistry. 2012 June 05, v. 51, no. 22

    2012  

    Abstract: At least four allosteric sites have been found to mediate the dose-dependent effects of gallamine on the binding of [³H]quinuclidinylbenzilate (QNB) and N-[³H]methylscopolamine (NMS) to M₂ muscarinic receptors in membranes and solubilized ... ...

    Abstract At least four allosteric sites have been found to mediate the dose-dependent effects of gallamine on the binding of [³H]quinuclidinylbenzilate (QNB) and N-[³H]methylscopolamine (NMS) to M₂ muscarinic receptors in membranes and solubilized preparations from porcine atria, CHO cells, and Sf9 cells. The rate of dissociation of [³H]QNB was affected in a bell-shaped manner with at least one Hill coefficient (nH) greater than 1, indicating that at least three allosteric sites are involved. The level of binding of [³H]QNB was decreased in a biphasic manner, revealing at least two allosteric sites; binding of [³H]NMS was affected in a triphasic, serpentine manner, revealing at least three sites, and values of nH >1 pointed to at least four sites. Several lines of evidence indicate that all effects of gallamine were allosteric in nature and could be observed at equilibrium. The rates of equilibration and dissociation suggest that the receptor was predominately oligomeric, and the heterogeneity revealed by gallamine can be attributed to differences in its affinity for the constituent protomers of a tetramer. Those differences appear to arise from inter- and intramolecular cooperativity between gallamine and the radioligand.
    Keywords dissociation ; dose response ; protein subunits ; receptors ; serpentine ; solubilization ; swine ; tritium
    Language English
    Dates of publication 2012-0605
    Size p. 4518-4540.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021%2Fbi3000287
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 217: Show issues Location:
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  3. Article ; Online: Heterotropic cooperativity within and between protomers of an oligomeric M(2) muscarinic receptor.

    Shivnaraine, Rabindra V / Huang, Xi-Ping / Seidenberg, Margaret / Ellis, John / Wells, James W

    Biochemistry

    2012  Volume 51, Issue 22, Page(s) 4518–4540

    Abstract: At least four allosteric sites have been found to mediate the dose-dependent effects of gallamine on the binding of [(3)H]quinuclidinylbenzilate (QNB) and N-[(3)H]methylscopolamine (NMS) to M(2) muscarinic receptors in membranes and solubilized ... ...

    Abstract At least four allosteric sites have been found to mediate the dose-dependent effects of gallamine on the binding of [(3)H]quinuclidinylbenzilate (QNB) and N-[(3)H]methylscopolamine (NMS) to M(2) muscarinic receptors in membranes and solubilized preparations from porcine atria, CHO cells, and Sf9 cells. The rate of dissociation of [(3)H]QNB was affected in a bell-shaped manner with at least one Hill coefficient (n(H)) greater than 1, indicating that at least three allosteric sites are involved. The level of binding of [(3)H]QNB was decreased in a biphasic manner, revealing at least two allosteric sites; binding of [(3)H]NMS was affected in a triphasic, serpentine manner, revealing at least three sites, and values of n(H) >1 pointed to at least four sites. Several lines of evidence indicate that all effects of gallamine were allosteric in nature and could be observed at equilibrium. The rates of equilibration and dissociation suggest that the receptor was predominately oligomeric, and the heterogeneity revealed by gallamine can be attributed to differences in its affinity for the constituent protomers of a tetramer. Those differences appear to arise from inter- and intramolecular cooperativity between gallamine and the radioligand.
    MeSH term(s) Allosteric Regulation/drug effects ; Allosteric Site ; Animals ; CHO Cells ; Cholinergic Antagonists/pharmacology ; Cricetinae ; Gallamine Triethiodide/pharmacology ; Kinetics ; Muscarinic Antagonists/pharmacology ; N-Methylscopolamine/pharmacology ; Protein Subunits/antagonists & inhibitors ; Protein Subunits/chemistry ; Protein Subunits/metabolism ; Quinuclidinyl Benzilate/pharmacology ; Receptor, Muscarinic M2/antagonists & inhibitors ; Receptor, Muscarinic M2/chemistry ; Receptor, Muscarinic M2/metabolism ; Sf9 Cells ; Solubility ; Swine
    Chemical Substances Cholinergic Antagonists ; Muscarinic Antagonists ; Protein Subunits ; Receptor, Muscarinic M2 ; Quinuclidinyl Benzilate (6581-06-2) ; Gallamine Triethiodide (Q3254X40X2) ; N-Methylscopolamine (VDR09VTQ8U)
    Language English
    Publishing date 2012-05-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/bi3000287
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 217: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  4. Article: Site-Directed Mutagenesis Implicates a Threonine Residue in TM6 in the Subtype Selectivities of UH-AH 37 and Pirenzepine at Muscarinic Receptors

    Ellis, John / Seidenberg, Margaret

    Pharmacology

    2000  Volume 61, Issue 2, Page(s) 62–69

    Abstract: The structural basis for the selectivity of the antagonist UH-AH 37 at human muscarinic acetylcholine receptors was investigated by expressing mutant receptors in COS-7 cells. Previous studies have demonstrated that the interaction between UH-AH 37 and [ ... ...

    Institution Departments of Psychiatry and Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pa., USA
    Abstract The structural basis for the selectivity of the antagonist UH-AH 37 at human muscarinic acetylcholine receptors was investigated by expressing mutant receptors in COS-7 cells. Previous studies have demonstrated that the interaction between UH-AH 37 and [3H]N-methylscopolamine in equilibrium assays is competitive and that the high affinity of UH-AH 37 for the M5 subtype, compared to M2, is due to an epitope in the sixth transmembrane domain (TM6) or the third outer loop of the receptor. By mutating each nonconserved residue in this region of M2 and M5 to its counterpart in the other receptor, we identified a threonine residue in the middle of TM6 uniquely responsible for the higher affinity of the M5 receptor (M1, M3, and M4 receptors also carry a threonine at that location and also have high affinity for UH-AH 37). The mutant receptor in which the corresponding alanine of the M2 receptor was replaced by threonine, M2401ala ⇒ thr, expressed enhanced affinity for pirenzepine as well as for UH-AH 37. The chick M2 receptor, which expresses anomalously high affinity for pirenzepine, differs from its mammalian counterparts by the presence of a threonine at this position. Affinities of AF-DX 116 and 4-DAMP, as well as the allosteric potency of UH-AH 37, were not sensitive to the M2401 ala ⇒ thr mutation.
    Keywords Receptors, muscarinic ; Mutagenesis ; Amino acid sequence ; Threonine ; UH-AH 37 ; Pirenzepine ; 4-DAMP ; AF-DX 116
    Language English
    Publishing date 2000-08-14
    Publisher S. Karger AG
    Publishing place Basel, Switzerland
    Document type Article
    Note Original Paper
    ZDB-ID 206671-3
    ISSN 1423-0313 ; 0031-7012
    ISSN (online) 1423-0313
    ISSN 0031-7012
    DOI 10.1159/000028382
    Database Karger publisher's database

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 332: Show issues Location:
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