Science for Health
Living cells are delimited by a membrane which isolates their internal machinery from the external world. However, cells such as the neurons which form the information-transduction networks of the brain must still be able to respond to incoming chemical signals. The 7-transmembrane helix G protein-coupled receptors (GPCRs) are a superfamily of genetically-encoded nanomachines that have evolved to enable this. Since GPCRs are the targets of about 40% of clinically prescribed drugs, a detailed understanding of their structures and molecular mechanisms of action is essential for the modern program of rational drug development.
Muscarinic acetylcholine receptors (mAChRs) regulate the activity of over 50% of the nerve cells in the brain. Recently, we have used targeted mutations of the M1 mAChR, a major mediator of cortical attention mechanisms, to show how a binding site for highly-selective activating agents may be created by a novel conformational isomerisation of a tryptophan side-chain. Such agonist ligands are targeted at the cognitive defects in Alzheimer’s and schizophrenia. We are making stable ligand complexes of M1 mAChRs, using both pharmacological and mutational methods, working towards an atomic resolution structure by X-ray crystallography. This will provide a starting point for quantitative molecular dynamics calculations of drug-receptor interactions.
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Conformational isomerisation of the side-chain of tryptophan 101 (purple) creates a binding pocket for the M1-selective antagonist 77-LH-28-1: (a) trans (b) gauche
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