Antagonist Binding to H1 Histamine Receptor

The newly obtained crystal structure of H1 histamine receptor (H1R) by Shimamura et al. reveals the doxepin-binding cavity. Doxepin is a tricyclic antidepressant, widely prescribed before the popularisation of SSRI.
Enjoy the views below.

PDB file: 3RZE
Structure of the human histamine H1 receptor in complex with doxepin.
Nature 2011 Jun 22. doi: 10.1038/nature 10236.
Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S.

Molecule: a chimeric human H1R with lysozyme
Lengths: 452 amino acids
Method: X-ray diffraction, 3.10 angstrom resolution
Ligand: Doxepin on PubChem

The over all view from the extracellular space. The colour code: rainbow gradient from dark blue (TM1) to red (helix 8); ligand (doxepin) in white, and phosphate ion in orange with oxygens in red.


Close-up views….
Viewed from TM2 and TM3 sides. The residues numbered with Ballesteros & Weinberg scheme applicable for Family A GPCRs.


Viewed from TM3 side, slightly tilted to see the cavity from the extracellular side.
See how Lys 5.39 and Tyr 6.55 interacting to close the cavity as if to capture the bound-antagonist momentarily in the antagonist-stabilised form. Tyr 3.33 and Trp 4.56 also joins the hydrophobic gatherings.