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Structure of the human histamine H1 receptor complex with doxepin

DOI: 10.1038/nature10236 DOI Help
PMID: 21697825 PMID Help

Authors: Tatsuro Shimamura (Japan Science and Technology Agency; Kyoto University; The Scripps Research Institute) , Mitsunori Shiroishi (Japan Science and Technology Agency; Kyoto University; Kyushu University) , Simone Weyand (Japan Science and Technology Agency; Imperial College London; Diamond Light Source) , Hirokazu Tsujimoto (Japan Science and Technology Agency; Kyoto University) , Graeme Winter (Diamond Light Source) , Vsevolod Katritch (University of California, San Diego) , Ruben Abagyan (University of California, San Diego) , Vadim Cherezov (The Scripps Research Institute) , Wei Liu (The Scripps Research Institute) , Gye Won Han (The Scripps Research Institute) , Takuya Kobayashi (Japan Science and Technology Agency; Kyoto University) , Raymond C. Stevens (The Scripps Research Institute) , So Iwata (Japan Science and Technology Agency; Kyoto University; Imperial College London; Diamond Light Source; RIKEN)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 475 , PAGES 65 - 70

State: Published (Approved)
Published: June 2011
Diamond Proposal Number(s): 316

Abstract: The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H1 receptor (H1R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H1R complex with doxepin, a first-generation H1R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp 4286.48, a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H1R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys 1915.39 and/or Lys 179ECL2, both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H1R antagonist specificity against H1R.

Journal Keywords: Crystallography; X-Ray; Doxepin; Histamine; Humans; Hydrophobic; Isomerism; Ligands; Models; Molecular; Phosphates; Protein; Receptors; Adrenergic; beta-2; Receptors; Dopamine; Receptors; Histamine; Substrate Specificity

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Membrane Protein Laboratory (MPL)
Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 29/07/2011 13:01

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech Allergic Diseases

Technical Tags:

Diffraction Macromolecular Crystallography (MX)