Researchers in Japan have solved the structure of a complex between the antihistamine drug doxepin and its target receptor histamine H1 receptor (H1R)1. Led by So Iwata of Kyoto University and the RIKEN Systems and Structural Biology Center in Yokohama, the team’s findings should aid the development of better treatments for allergies and inflammation.
Figure 1: The crystal structure of H1R with bound doxepin, showing the position of tryptophan and phosphate. Copyright : 2011 So Iwata
Histamine, which is released by mast cells of the immune system, is an important mediator of allergic and inflammatory reactions. It exerts its effects by activating cell-surface receptors, thereby triggering cell signaling events. Of the four known human histamine receptor types, H1R is expressed by various tissues, including airways, the vasculature, and the brain.
Pharmacologists have developed various antihistamine drugs that interfere with histamine–receptor interactions. “Many of us will have taken antihistamines to alleviate the symptoms of hay fever, for example, or to stop the swelling and itchiness caused by insect bites,” Iwata says.
Iwata and his collaborators solved the structure of H1R with bound doxepin using x-ray crystallography. Like all proteins, H1R is composed of amino-acid building blocks. The amino acid tryptophan is found at a particular position in H1R and is known to be important for receptor activation. The researchers revealed that doxepin sits deep within a binding pocket in the receptor, where it interacts directly with this key amino acid (Fig. 1), helping to explain its pharmacological activity.
Doxepin was one of the first antihistamines that effectively blocks histamine receptor activation. Unfortunately, however, these drugs also bind other related receptors. “This low selectivity along with their ability to enter the brain means that these first-generation drugs have considerable side effects such as sedation, mouth dryness, and heart arrhythmias,” explains Iwata.
The researchers’ structural findings suggested that the low selectivity of doxepin is due to the hydrophobic (‘water hating’) nature of the binding pocket, a characteristic found in other receptors to which the drug binds. However, they found that the binding pocket of H1R has a distinctive region occupied by the negatively charged ion phosphate. Through molecular modeling, they demonstrated that the second-generation drugs such as olopatadine would interact with this region, which is not conserved in other related receptors. This explains why these drugs are more selective and have fewer side effects compared with doxepin.
“Our findings demonstrate how minor differences in receptors affect drug selectivity and will be useful in the development of the next generation of antihistamines,” says Iwata.Reference:
Not of Divided Mind
19.01.2017 | Hertie-Institut für klinische Hirnforschung (HIH)
CRISPR meets single-cell sequencing in new screening method
19.01.2017 | CeMM Forschungszentrum für Molekulare Medizin der Österreichischen Akademie der Wissenschaften
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
19.01.2017 | Earth Sciences
19.01.2017 | Life Sciences
19.01.2017 | Physics and Astronomy