Histamine receptor structure revealed

Add another G-protein-coupled receptor (GPCR) to the growing list of cell-membrane proteins for which researchers have determined a crystal structure. An international team, led by Raymond C. Stevens of Scripps Research Institute and So Iwata of Imperial College London, reports the structural details of histamine receptor H₁ bound to the antihistamine drug doxepin in Nature (DOI: 10.1038/nature10236). The H₁ receptor is a key player in the mechanics of inflammation and itch caused by allergens and is therefore a popular target for drug discovery. Antihistamine drugs act by binding to the receptor and blocking its activation by the natural ligand, histamine. The researchers hope that the new structural details of the receptor will aid the development of antihistamines with fewer side effects. The crystal structure shows that doxepin sits more deeply in the receptor’s binding pocket than do ligands in other GPCR structures. The drug also clearly interacts with a tryptophan residue on one of the H₁ receptor’s helices that has “long been thought to be involved in GPCR activation” but never confirmed to do so, says Rob Leurs, a medicinal chemist at the Free University of Amsterdam.