3D picture of histamine receptor may lead to improved antihistamines

An international team of scientists using Diamond Light Source, the UK's national synchrotron facility, has successfully solved the complex 3D structure of the human histamine H1 receptor protein.

Published in the journal 'Nature' this week, their structure opens the way for the development of 'third-generation' antihistamines, specific drugs effective against various allergies without causing adverse side-effects.

The H1 receptor protein is found in the cell membranes of various human tissues including airways, vascular and intestinal muscles, and the brain. It binds to histamine and has an important function in the immune system, but in susceptible individuals this can cause allergic reactions such as hay fever, food allergies and pet allergies. Antihistamine drugs work because they prevent histamine attaching to H1 receptors.

Dr Simone Weyand, postdoctoral scientist at Imperial College London, who conducted much of the experimental work at Diamond, said: "First-generation antihistamines such as doxepin are effective, but not very selective, and because of penetration across the blood-brain barrier, they can cause side-effects including sedation, dry mouth and arrhythmia. By showing exactly how histamines bind to the H1 receptor at the molecular level, we can design and develop much more targeted treatments."

A team comprising leading experts from The Scripps Research Institute in California (USA), Kyoto University (Japan), Imperial College London and Diamond worked for 16 months on the project.

Professor So Iwata, Director of the Membrane Protein Laboratory at Diamond, said: "It took a considerable team effort but we were finally able to elucidate the molecular structure of the histamine H1 receptor protein and also see how it interacts with antihistamines. This detailed structural information is a great starting point for exploring exactly how histamine triggers allergic reactions and how drugs act to prevent this reaction."

Diamond scientists analysed more than 700 samples using the Microfocus Macromolecular Crystallography (MX) beamline I24, a unique instrument capable of studying tiny microcrystals using an X-ray beam a few microns wide.

Prof Iwata added: "The fact that we've managed to solve this structure in 16 months starting from pure protein is very exciting as it shows what can be achieved when a team of experts pool skills and experience in sample preparation, experimental techniques and data analysis.

"Having the Membrane Protein Laboratory situated inside the Diamond synchrotron itself is a major advantage for projects like this. We've benefited from rapid-access to the beamline and round-the-clock support for our experiments and data analysis work."

The result of collaboration between the Wellcome Trust and the UK Government, Diamond is the largest UK-funded scientific facility to be built for more than 40 years.