The structure and activity of membrane receptors: Computational simulation of histamine H<inf>2</inf>-receptor activation

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Abstract

A three dimensional molecular model of the transmembrane domain of the Histamine H2-receptor was constructed, by computer-aided model building techniques, based on the amino acid sequence; topological criteria guided by inferences from sequence homologies; the electron density projection map of bovine Rhodopsin obtained from electron microscopy; prediction of helix - helix interactions; experimental results from site-directed mutagenesis; and quantum mechanical calculations. In this model, the binding of Histamine to the receptor consists of: i) the ionic interaction between the protonated side chain amine and the conserved Asp98, located in transmembrane helix (TMH) 3; ii) the hydrogen bond between the N(3)-H moiety of the imidazole ring and the non conserved Asp186, located in TMH 5; and iii) the hydrogen bond between the N(1) atom of the imidazole ring and the non conserved Arg257, located in TMH 6. The activation mechanism of the receptor resulting from ligand binding takes the form of a proton transfer from TMH 6 (Arg257) to TMH 5 (Asp186). 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 signal, encoded in the structure of the ligand, to the intracellular site.
Original languageEnglish
Pages (from-to)279-286
JournalJournal of Molecular Structure: THEOCHEM
Volume371
DOIs
Publication statusPublished - 18 Nov 1996

Keywords

  • Ab initio calculation
  • G protein-coupled receptor
  • Histamine H -receptor 2
  • Membrane receptor

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