THE STRUCTURE AND ACTIVITY OF MEMBRANE-RECEPTORS - COMPUTATIONAL SIMULATION OF HISTAMINE H-2-RECEPTOR ACTIVATION

A three dimensional molecular model of the transmembrane domain of the Histamine Ha-receptor was constructed, by computer-aided model buildi ng techniques, based on the amino acid sequence; topological criteria guided by inferences from sequence homologies; the electron density pr ojection map of bovine Rhodopsin obtained from electron microscopy; pr ediction of helix-helix interactions; experimental results from site-d irected mutagenesis; and quantum mechanical calculations. In this mode l, the binding of Histamine to the receptor consists of: i) the ionic interaction between the protonated side chain amine and the conserved Asp(98), located in transmembrane helix (TMH) 3; ii) the hydrogen bond between the N(3)-H moiety of the imidazole ring and the non conserved Asp(186), located in TMH 5; and iii) the hydrogen bond between the N( 1) atom of the imidazole ring and the non conserved Arg(257), located in TMB 6. The activation mechanism of the receptor resulting from liga nd binding takes the form of a proton transfer from TMH 6 (Arg(257)) t o TMH 5 (Asp(186)). This process explains the local changes induced by agonist in the receptor binding site. The structural consequences of these changes could mediate the propagation of the extracellular signa l, encoded in the structure of the ligand, to the intracellular site.