PMID: 9443945Jan 28, 1998Paper

Steric hindrance mutagenesis versus alanine scan in mapping of ligand binding sites in the tachykinin NK1 receptor

Molecular Pharmacology
Birgitte HolstThue W Schwartz

Abstract

Residues in transmembrane domain (TM)-III, TM-V, TM-VI, and TM-VII believed to be facing the deep part of the presumed main ligand-binding pocket of the NK1 receptor were probed by alanine substitution and introduction of residues with larger and/or chemically distinct side chains. Unaltered or even improved binding affinity for four peptide agonists, substance P, substance P-O-methyl ester, eledoisin, and neurokinin A, as well as normal EC50 values for substance P in stimulating phosphatidylinositol turnover indicated that these mutations did not alter the overall functional integrity of the receptor. The alanine substitutions in general had only minor effects on nonpeptide antagonist binding. However, the introduction of the larger and polar aspartic acid and histidine residues at positions corresponding to the monoamine binding aspartic acid in TM-III of the beta 2-adrenoceptor (ProIII:08, Pro112 in the NK1 receptor) and to the presumed monoamine interacting "two serines" in TM-V (ThrV:09, Thr201; and IleV:12, Ile204) impaired by > 100-fold the binding of a group of nonpeptide antagonists, including CP96,345, CP99,994, RP67,580, RPR100,893, and CAM4092. In contrast, another group of nonpeptide antagonists, LY303,870, FK888, ...Continue Reading

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Citations

Aug 31, 2002·Journal of Molecular Recognition : JMR·Sarah BhargavaRudolf Volkmer-Engert
Dec 31, 2002·Journal of Receptor and Signal Transduction Research·A HedingT W Schwartz
Oct 31, 2003·The Journal of Biological Chemistry·Mette M RosenkildeThue W Schwartz
Jun 12, 2004·Journal of Biomolecular Screening·Milka VreclAnders Heding
Apr 4, 2007·Journal of Neurochemistry·Sannah ZoffmannJean-Luc Galzi
Feb 12, 2011·The Journal of Biological Chemistry·Manuela GebhardtGerhard Thiel
Aug 30, 2000·Proceedings of the National Academy of Sciences of the United States of America·S M NielsenW W Vale
Apr 1, 2006·Chembiochem : a European Journal of Chemical Biology·Jana PrzezdziakRudolf Volkmer-Engert
Sep 24, 2004·The Journal of Biological Chemistry·Birgitte HolstThue W Schwartz
Apr 17, 2010·The Journal of Biological Chemistry·Rie NygaardThue W Schwartz
Aug 7, 2012·Endocrinology·Kristy M HeppnerMatthias H Tschöp
Aug 25, 2015·Biopolymers·Anjali Ganjiwale, Sudha M Cowsik
Aug 24, 2001·Archives of Insect Biochemistry and Physiology·H TorfsR J Nachman
Jan 13, 2006·Annual Review of Pharmacology and Toxicology·Thue W SchwartzChristian E Elling
Aug 25, 2004·Proteins·Sharon ShachamOren M Becker
Jun 30, 2007·The Journal of Biological Chemistry·Mette M RosenkildeThue W Schwartz
Jan 13, 2010·The Journal of Pharmacology and Experimental Therapeutics·F GbahouT W Schwartz
Nov 9, 2012·The Journal of Biological Chemistry·Louise Valentin-HansenThue W Schwartz
Mar 16, 2011·The Journal of Biological Chemistry·Bjørn SivertsenBirgitte Holst
May 17, 2014·The Journal of Biological Chemistry·Louise Valentin-HansenThomas P Sakmar
Sep 21, 2010·Journal of Peptide Science : an Official Publication of the European Peptide Society·Søren L PedersenNiels Vrang
Jan 4, 2019·Nature Communications·Jendrik SchöppeAndreas Plückthun
Feb 13, 2001·Journal of Internal Medicine·T HökfeltJ Wahren
Nov 19, 2009·The Journal of Biological Chemistry·Birgitte HolstThue W Schwartz
Aug 28, 2013·Chemical Reviews·Robert O J Weinzierl
Sep 15, 2011·Journal of Chemical Information and Modeling·Anjali D GanjiwaleSudha M Cowsik

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