MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Allman, K.
Right arrow Articles by Hulme, E. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Allman, K.
Right arrow Articles by Hulme, E. C.

Vol. 58, Issue 1, 175-184, July 2000

Scanning Mutagenesis Identifies Amino Acid Side Chains in Transmembrane Domain 5 of the M1 Muscarinic Receptor that Participate in Binding the Acetyl Methyl Group of Acetylcholine

Karen Allman,1 Karen M. Page,2 Carol A.M. Curtis, and Edward C. Hulme

Division of Physical Biochemistry, Medical Research Council National Institute for Medical Research, London, United Kingdom

The exofacial part of transmembrane domain 5 (TMD 5) of the cationic amine-binding subclass of 7-transmembrane receptors is thought to be important in binding the side chain of the agonist. Residues Ile-188 through Ala-196 in TMD 5 of the M1 muscarinic acetylcholine receptor (mAChR) have been studied by Cys- and Ala-scanning mutagenesis. The results are consistent with a helical conformation for this sequence. The positively charged sulfhydryl reagent N-trimethyl-2-aminoethyl methanethiosulfonate reacted selectively with Phe-190 right-arrow Cys, Thr-192 right-arrow Cys, and Ala-193 right-arrow Cys, indicating that the face of TMD 5 accessible from the binding site crevice is consistent with a recent model by Baldwin and colleagues of the transmembrane domain of the 7-transmembrane receptors. In contrast, the acetylcholine derivative bromoacetylcholine reacted selectively with Thr-192 right-arrow Cys, which forms the focus of a group of amino acids (Ile-188, Thr-189, Thr-192, Ala-196) whose mutation decreased the binding affinity of the transmitter ACh itself. The center of this patch of residues is offset to one side of the binding pocket, suggesting that a rotation of TMD 5, relative to that implied by the Baldwin model, may be necessary to optimize the anchoring of acetylcholine within the binding site of the M1 mAChR. An induced rotation of TMD 5 could contribute to the formation of the activated state of the receptor.

1 Current address: SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (South), Third Ave., Essex CM19 5AW, UK.

2 Current address: Department of Pharmacology, University College London, London WC1E 6BT, UK.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
J. A. Goodwin, E. C. Hulme, C. J. Langmead, and B. G. Tehan
Roof and Floor of the Muscarinic Binding Pocket: Variations in the Binding Modes of Orthosteric Ligands
Mol. Pharmacol., December 1, 2007; 72(6): 1484 - 1496.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. S. Bee and E. C. Hulme
Functional Analysis of Transmembrane Domain 2 of the M1 Muscarinic Acetylcholine Receptor
J. Biol. Chem., November 2, 2007; 282(44): 32471 - 32479.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S.-J. Han, F. F. Hamdan, S.-K. Kim, K. A. Jacobson, L. M. Bloodworth, B. Li, and J. Wess
Identification of an Agonist-induced Conformational Change Occurring Adjacent to the Ligand-binding Pocket of the M3 Muscarinic Acetylcholine Receptor
J. Biol. Chem., October 14, 2005; 280(41): 34849 - 34858.
[Abstract] [Full Text] [PDF]

Home page
 Chem SensesHome page
W. B. Floriano, N. Vaidehi, and W. A. Goddard III
Making Sense of Olfaction through Predictions of the 3-D Structure and Function of Olfactory Receptors
Chem Senses, May 1, 2004; 29(4): 269 - 290.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Berezhnoy, Y. Nyfeler, A. Gonthier, H. Schwob, M. Goeldner, and E. Sigel
On the Benzodiazepine Binding Pocket in GABAA Receptors
J. Biol. Chem., January 30, 2004; 279(5): 3160 - 3168.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
T. A. Spalding, C. Trotter, N. Skjarbak, T. L. Messier, E. A. Currier, E. S. Burstein, D. Li, U. Hacksell, and M. R. Brann
Discovery of an Ectopic Activation Site on the M1 Muscarinic Receptor
Mol. Pharmacol., June 1, 2002; 61(6): 1297 - 1302.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Z.-L. Lu, J. W. Saldanha, and E. C. Hulme
Transmembrane Domains 4 and 7 of the M1 Muscarinic Acetylcholine Receptor Are Critical for Ligand Binding and the Receptor Activation Switch
J. Biol. Chem., August 31, 2001; 276(36): 34098 - 34104.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics