Muscarinic receptors: a comparative analysis of structural features and binding modes through homology modelling and molecular docking

Three-dimensional models of the five human muscarinic receptors were obtained from their known sequences. Homol. modeling based on the crystallog. structure of bovine rhodopsin yielded models compatible with known results from site-directed mutagenesis studies. The only exceptions were the cytoplasmic loop 3 (CL3) in the five receptors, and the large C-terminal domain in M1. Here, homol. modeling with other closely related proteins allowed to solve these gaps. A detailed comparative discussion of the five models is given. The second part of the work involved docking expts. with the physiol. ligand acetylcholine, again yielding results entirely compatible with results from mutagenesis expts. The study revealed analogies and differences between the five receptors in the residues, and interactions leading to the recognition and binding of acetylcholine