A new method for determining the detailed architecture of key drug targets that relay vital messages into our cells could revolutionise the way we make and test drugs.
For decades it has been difficult to obtain information about the structure of proteins on the surface of cells that many drugs are designed to latch on to. However, a new approach, developed by scientists at the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, can reveal the precise structures of recombinant G protein-coupled receptors (GPCRs), proteins that cross the cell membrane and are important targets for drug development. This novel method will allow scientists developing drugs to compare the structure of highly similar drug receptor proteins, called receptor subtypes, and produce more selective drugs. It is thought the findings, published in Nature, could also apply to many other key proteins associated with cell membranes, which mediate other important physiological processes.
Dr Gebhard Schertler who led the research on G protein-coupled receptors at the Laboratory of Molecular Biology said: "We have been looking at these drug target proteins for a long time trying to find a way to capture their shape. It's a bit like trying to find a way to take a non-blurry picture of a child at play. By using a new approach called conformational stabilisation we were able to trap the receptor in a form bound to a beta blocker. We then stabilised the receptor proteins enough to obtain crystals. Using very small X-ray beams we obtained an image of the Гџ1 adrenergic receptor. The level of precision that we reached will allow the creation of drugs which will be able to bind more specifically. This means medicines with fewer side-effects."
The specific structure reported in this Nature paper is that of the adrenalin stress hormone receptor (Гџ1 adrenergic receptor) which regulates heart rate and blood pressure. This receptor is targeted by drugs commonly referred to as beta-blockers, which are used in the treatment of hypertension and heart palpitations. The team at the MRC was able to compare the structure of Гџ1 with Гџ2 adrenergic receptor. The Гџ2 adrenergic receptor is the target for drugs in inhalers used to contain asthma attacks; these Гџ adrenergic receptor activators dilate the bronchial muscles in the lung and airways by acting on the Гџ2 adrenergic receptor.
Dr Schertler explains how these comparisons will be useful: "The Гџ1 and Гџ2 adrenergic receptor targets belong to the same receptor class and have very similar structures. Until now, drugs that affected one receptor also affected the other to some degree. So using an inhaler, which is intended to stimulate Гџ2 receptors to contain asthma attacks, also stimulates the Гџ1 adrenergic receptors and causes the heart to beat faster. Better targeting of new drugs using these new structural insights should allow us to avoid such side effects in the future."
Structure of the stress hormone receptor Гџ1 with a beta blocker bound to it
Dr Gebhard Schertler added: "The quality of the structural data we have been able to produce using this new approach is excellent and we feel the method is so robust there is no reason to think we would not be able to produce similar results with hundreds of other receptors. This will not only allow us to devise drugs that are much more selective for a single receptor, it could potentially turn the drug discovery process on its head, starting with the G protein-coupled receptor you wish to affect, and devising a drug to bind to it. This is important because there are still a significant number of human receptors where we do not know of a existing substance able to bind to them."
These latest findings are the culmination of decades of work by Richard Henderson, Chris Tate, Gebhard Schertler and other researchers at the Medical Research Council. Their steady progress led to the creation of a biotechnological spin out company Heptares Therapeutics, a new drug discovery company that was formed in 2007. The aim of the company is to support the translation of the successful long-term basic research results by providing it with the right infrastructure and fostering application. This means bringing together first-class investors and management while keeping the founding scientists at the core of the company's future
MRC/28/08
Background
- Structure of a b1-adrenergic G-protein-coupled receptor
Warne et al (2008)
Nature Online doi:10.1038/nature07101
- The more than 800 GPCRs in man belong to the largest family of membrane proteins in the human genome. Their function is to sense molecules outside the cell, hence 'receptors', and trigger cellular reactions. GPCRs are essential for the body to complete a wide range of physiological responses. They allow us to process light and smells, regulate our behaviour, mood and immune response. They are essential in autonomic nervous system transmission. They also control blood pressure, heart rate and digestive processes. This means GPCRs play a crucial role in many diseases and are targets of around a quarter of all modern drugs and GPCRS are a major focus for pharmaceutical companies. For more information, visit the Schertler Group page : www2.mrc-lmb.cam.ac.uk/SS/Schertler_G/
For more information about Heptares, please visit heptares
Medical Research Council
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