Allosteric interactions with muscarinic acetylcholine receptors: complex role of the conserved tryptophan M2422Trp in a critical cluster of amino acids for baseline affinity, subtype selectivity, and cooperativity.

Molecular Pharmacology
Stefanie PrillaK Mohr

Abstract

In general, the M2 subtype of muscarinic acetylcholine receptors has the highest sensitivity for allosteric modulators and the M5 subtype the lowest. The M2/M5 selectivity of some structurally diverse allosteric agents is known to be completely explained by M2 177Tyr and M2 423Thr in receptors whose orthosteric site is occupied by the conventional ligand N-methylscopolamine (NMS). This study explored the role of the conserved M2 422Trp and the adjacent M2 423Thr in the binding of alkane-bisammonio type modulators, gallamine, and diallylcaracurine V. Experiments were performed with human M2 or M5 receptors or mutants thereof. It was found that M2 422Trp and M2 423Thr independently influenced allosteric agent binding. The presence of M2 423Thr may enhance the affinity of binding, depending on the allosteric agent, either directly or indirectly (by avoiding sterical hindrance through its M5 counterpart 478His). Replacement of M2 422Trp and of the corresponding M5 477Trp by alanine revealed a pronounced contribution of these epitopes to subtype independent baseline affinity in NMS-bound and NMS-free receptors for all agents except diallylcaracurine V. In a few instances, this tryptophan also influenced cooperativity and subtype sel...Continue Reading

References

Nov 1, 1976·British Journal of Pharmacology·A L Clark, F Mitchelson
Apr 19, 2002·The Journal of Pharmacology and Experimental Therapeutics·Katrin ZahnKlaus Mohr
May 31, 2002·Pharmacological Reviews·Arthur Christopoulos, Terry Kenakin
Jun 27, 2003·Journal of Computer-aided Molecular Design·Kirstin Jöhren, Hans-Dieter Höltje
Aug 2, 2003·Receptors & Channels·K MohrU Holzgrabe
Aug 26, 2004·Journal of Molecular Biology·Tetsuji OkadaVolker Buss
Sep 29, 2004·Drug Discovery Today·Willem SoudijnAd P IJzerman
Jun 25, 2005·Mini Reviews in Medicinal Chemistry·N J M Birdsall, S Lazareno
Sep 27, 2005·Molecular Pharmacology·Jürgen Wess

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Citations

Jul 3, 2013·Journal of Computer-aided Molecular Design·Jan JakubíkVladimír Doležal
Nov 27, 2009·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Katie LeachArthur Christopoulos
Jan 1, 2009·Nature Reviews. Drug Discovery·P Jeffrey ConnCraig W Lindsley
Dec 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Noa DekelFrancisco Bezanilla
Oct 1, 2010·Pharmaceuticals·Naveena Yanamala, Judith Klein-Seetharaman
Aug 30, 2010·Pharmaceuticals·Jan Jakubík, Esam E El-Fakahany
Feb 9, 2010·British Journal of Pharmacology·Klaus MohrUlrike Holzgrabe
May 28, 2014·Biochemical Pharmacology·Ramona SchrageKlaus Mohr
Jun 2, 2006·International Review of Neurobiology·Rüdiger SchweigreiterRobert M Gould
Feb 9, 2017·Molecular Pharmacology·Anna De MinRamona Schrage
Jan 21, 2014·The Journal of Biological Chemistry·Alaa Abdul-RidhaArthur Christopoulos
May 26, 2007·Molecular Pharmacology·Lauren T MayArthur Christopoulos
Jul 25, 2019·Nature Communications·Scott A HollingsworthRon O Dror
Nov 22, 2013·Nature·Andrew C KruseBrian K Kobilka
Nov 28, 2019·Proceedings of the National Academy of Sciences of the United States of America·Ziva VuckovicDavid M Thal
Jun 15, 2016·The Journal of Biological Chemistry·Andreas BockKlaus Mohr
Oct 10, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Johannes AntonyKlaus Mohr
Oct 3, 2006·Annual Review of Pharmacology and Toxicology·Lauren T MayArthur Christopoulos
Jul 10, 2009·Journal of Receptor and Signal Transduction Research·Anna KebigMarion Mohr-Andrä
May 11, 2011·Future Medicinal Chemistry·Christofer S Tautermann
Nov 12, 2013·Nature Chemical Biology·Andreas BockKlaus Mohr
Aug 2, 2013·Nature Reviews. Drug Discovery·Denise WoottenPatrick M Sexton
Oct 20, 2007·Journal of Medicinal Chemistry·Paul W ElsinghorstMichael Gütschow
Aug 6, 2021·ACS Chemical Neuroscience·Wessel A C BurgerDavid M Thal
Jul 23, 2014·Journal of Medicinal Chemistry·Jens SchmitzUlrike Holzgrabe
Jul 11, 2021·The Journal of Pharmacology and Experimental Therapeutics·Risa OkimotoNaoki Yoshimura

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