A homology model of the M1 muscarinic acetylcholine receptor, based on the X-ray structure of bovine rhodopsin, has been used to interpret the results of scanning and point mutagenesis studies on the receptor's transmembrane (TM) domain. Potential intramolecular interactions that are important for the stability of the protein fold have been identified. The residues contributing to the binding site for the antagonist, N-methyl scopolamine, and the agonist, acetylcholine, have been mapped. The positively charged headgroups of these ligands probably bind in a charge-stabilized aromatic cage formed by amino acid side chains in TM helices TM3, TM6 and TM7, while residues in TM4 may participate as part of a peripheral docking site. Closure of the cage around the headgroup of acetylcholine may be part of the mechanism for transducing binding energy into receptor activation, probably by disrupting a set of Van der Waals interactions between residues lying beneath the binding site that help to constrain the receptor to the inactive state, in the absence of agonist. This may trigger the reorganization of a hydrogen-bonding network between highly conserved residues in the core of the receptor, whose integrity is crucial for achievement of the activated state.
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February 2003
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Conference Article|
February 01 2003
Structure and activation of muscarinic acetylcholine receptors
E.C. Hulme;
E.C. Hulme
1
*Division of Physical Biochemistry, National Institute for Medical Research, Mill Hill, London NW7 1AA, U.K.
1To whom correspondence should be addressed (ehulme@nimr.mrc.ac.uk).
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Z.L. Lu;
Z.L. Lu
†MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh, Academic Centre, 49 Little France Crescent, Edinburgh EH16 4SB, U.K.
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J.W. Saldanha;
J.W. Saldanha
‡Department of Mathematical Biology, National Institute for Medical Research, Mill Hill, London NW7 1AA, U.K.
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M.S. Bee
M.S. Bee
†MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh, Academic Centre, 49 Little France Crescent, Edinburgh EH16 4SB, U.K.
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
Copyright 2003 Biochemical Society
2003
Biochem Soc Trans (2003) 31 (1): 29–34.
Citation
E.C. Hulme, Z.L. Lu, J.W. Saldanha, M.S. Bee; Structure and activation of muscarinic acetylcholine receptors. Biochem Soc Trans 1 February 2003; 31 (1): 29–34. doi: https://doi.org/10.1042/bst0310029
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