Histamine H1 receptor breakthrough heralds improved allergy treatments
New 3D picture of human membrane protein enables development of targeted anti-histamines without side-effects.
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 (pictured right). Published in the journal Nature this week, their discovery opens the way for the development of ‘third generation’ anti-histamines, specific drugs effective against various allergies without causing adverse side-effects.
The team, comprising leading experts from the USA (The Scripps Research Institute in California), Japan (Kyoto University), and the UK (Imperial College London and Diamond), worked across three continents for 16 months on the project.
Professor So Iwata, David Blow Chair of Biophysics at Imperial College London, BBSRC Fellow and Director of the Membrane Protein Laboratory at Diamond
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, an important function of the immune system, but in susceptible individuals this can cause allergic reactions such as hay fever, food and pet allergies. Anti-histamine drugs work because they prevent histamine attaching to H1 receptors.
Dr Simone Weyand, post-doctoral scientist at Imperial College London
The research was technically challenging because membrane proteins are notoriously difficult to crystallise – a step that is vital in solving protein structures using a synchrotron. The protein was produced in cells at Kyoto University in Japan, then processed cell material was flown to Professor Raymond Stevens at The Scripps Research Institute in La Jolla, California, who leads the GPCR Network of the National Institute of General Medical Sciences' Protein Structure Initiative, and has developed powerful techniques to analyse membrane proteins and crystallise G-protein coupled receptors (GPCRs) funded by the National Institutes of Health Common Fund.
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.”
Right: Prof So Iwata and Dr Simone Weyand working on the Microfocus Macromolecular Crystallography beamline at Diamond Light Source
Professor Gerd Materlik, Diamond’s Chief Executive
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‘Structure of the human histamine H1 receptor complex with doxepin’
Tatsuro Shimamura, Mitsunori Shiroishi, Simone Weyand, Hirokazu Tsujimoto, Graeme Winter, Vsevolod Katritch, Ruben Abagyan, Vadim Cherezov, Wei Liu, GyeWon Han, Takuya Kobayashi, Raymond C. Stevens & So Iwata.
Nature, 22 June 2011