Good news for summer: Hayfever X-rayed

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  • Published: Jul 1, 2011
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Good news for summer: Hayfever X-rayed

Allergic structure

There is potentially welcome news for hayfever sufferers as researchers have now obtained an X-ray crystal structure of the human histamine H1 receptor (H1R). The team reported details in the journal Nature in June and suggest that the structure could help in the development of novel antihistamine drugs.

An international team research team has used the UK's Diamond Light Source synchrotron facility to discern the three-dimensional structure of the human histamine H1 receptor protein. The work could lead the way to "third generation" antihistamines compounds that are more targeted against allergies and have fewer side-effects, such as drowsiness, than many conventional medications used by hayfever sufferers and others with allergic rhinitis and related conditions.

"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 anti-histamines. 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," explains So Iwata, who is David Blow Chair of Biophysics at Imperial College London and Director of the Membrane Protein Laboratory at Diamond as well as being a member of the Japanese research organisation ERATO.

An interesting reception

The H1 receptor is found in the cell membranes of numerous human tissues including those lining the airways, vascular and intestinal muscles and in the brain. Its immunological role involves the recognition and binding of the histamine molecule, which in turn ultimately triggers various biochemical and immunological responses such as increased mucus production, inflammation and narrowing of the airways. In susceptible individuals, however, the response can swing too far towards the protective and gives rise to what we refer to as an allergic reaction, such as the well-known symptoms of hayfever, food and pet allergies, including runny nose, itchy throat, sore and bloodshot eyes, breathlessness and in extreme cases anaphylaxis.

Antihistamine drugs were developed to modulate this response and many work simply by blocking the H1 receptor and preventing histamine from finding its target. The first generation of antihistamine drugs, such as Doxepin, are effective in this regard but they are unfortunately not particularly selective for the relevant receptors. They can penetrate the blood-brain barrier and induce side effects such as sedation, dry mouth and sometimes heart problems like arrhythmia. "By showing exactly how histamines bind to the H1 receptor at the molecular level, we can design and develop much more targeted treatments," team member Simone Weyand of Imperial College explains.

Membrane proteins are infamous for the technical challenges they present to crystallographers, not least the fact that that they rarely form suitable crystals if they form any crystals at all.

"Membrane proteins exist in both a hydrophobic and hydrophilic world (most of the protein is in the membrane (hydrophobic) but part is also outside of the membrane and thus dual nature makes it really difficult to crystallize the proteins," Stevens told SpectroscopyNOW. "In addition, expression is typically very challenging since the membrane is a smaller percentage of the overall cell, and overexpression of proteins in the membrane usually cause cell toxicity."

Nevertheless the team persevered with producing the proteins in cells at Kyoto University with a view to sending the processed cell material to Raymond Stevens at The Scripps Research Institute in La Jolla, California. Stevens has developed powerful techniques for analysing membrane proteins and crystallising G-protein coupled receptors (GPCRs). Crystal growth took about two months and the solid products were then frozen and sent to Diamond. Iwata and Weyand then worked with the Diamond team to analyse a total of over 700 samples of the micro-crystals using an X-ray beam a few micrometres wide.

Receptor focus

"A key aspect of our program is to collaborate with the leading researchers in the world so that we can uncover the mysteries of how GPCRs work," Stevens explains." To fully understand this large and important human protein family will take a global community effort and the study of multiple receptors with different techniques and approaches." Iwata adds that, "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. We've benefited from rapid-access to the beamline and round the clock support for our experiments and data analysis work."

As to whether or not the X-ray structure represents the membrane protein in a near-natural state. Stevens points out that, "Protein crystals are typically 50-70% solvent, and thus it is not a locked in solid state crystal.  We see lots of flexibility in the crystal structures," he adds.

The team includes: Tatsuro Shimamura , Mitsunori Shiroishi, Simone Weyand, Hirokazu Tsujimoto, Takuya Kobayashi and So Iwata of the Human Receptor Crystallography Project, at ERATO, Japan Science and Technology Agency in Kyoto, Japan, Graeme Winter of the Diamond Light Source, at Harwell Science and Innovation Campus, in Chilton, Didcot, UK, Vsevolod Katritch, Ruben Abagyan of Skaggs School of Pharmacy and Pharmaceutical Sciences and San Diego Supercomputer Center, at the University of California, San Diego, and Vadim Cherezov, Wei Liu, Gye Won Han and Raymond Stevens of the Department of Molecular Biology, at The Scripps Research Institute, in La Jolla, California, USA.

 



The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

 There is potentially welcome news for hayfever sufferers as researchers have now obtained an X-ray crystal structure of the human histamine H1 receptor (H1R). The team reported details in the journal Nature in June and suggest that the structure could help in the development of novel antihistamine drugs.

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