MODELING OF THE BINDING-SITE OF THE HUMAN M(1) MUSCARINIC RECEPTOR - EXPERIMENTAL VALIDATION AND REFINEMENT

Our model of the human m(1) muscarinic receptor has been refined on th e basis of the recently published projection map of bovine rhodopsin. The refined model has a slightly different helix arrangement, which re veals the presence of an extra hydrophobic pocket located between heli ces 3, 4 and 5. The interaction of series of agonists and antagonists with the m(1) muscarinic receptor has been studied experimentally by s ite-directed mutagenesis. In order to account for the observed results , three-dimensional models of m(1) ligands docked in the target recept or are proposed. Qualitatively, the obtained models are in good agreem ent with the experimental observations. Agonists and partial agonists have a relatively small size. They can bind to the same region of the receptor using, however, different anchoring receptor residues. Antago nists are usually larger molecules, filling almost completely the same pocket as agonists. They can usually produce much stronger interactio ns with aromatic residues. Experimental data combined with molecular m odelling studies highlight how subtle and diverse receptor-ligand inte ractions could be.