Breakthrough reveals important human receptor structure that will aid drug development

Oct 22 2007

Scientists at the MRC Laboratory of Molecular Biology (LMB) in Cambridge have obtained the first clear images of the proteins that relay vital messages to cells.

G protein-coupled receptors (GPCRs) bridge the cell membrane, relaying crucial information from the outside of the cell to the inside. They constitute a major target for drug development. Now scientists have been able to produce and crystallise GPCRs and obtain the first structure of a recombinant GPCR using a method known as high brilliance microcrystallography. Their findings are published in Nature.

The 700 or so GPCRs in man belong to the largest family of cell 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 half of all modern drugs and a major focus for pharmaceutical companies.

There has been significant progress in understanding GPCRs over the last two decades, including important work on their structure by Dr Gebhard Schertler and colleagues at the LMB, yet little was known about how its structure influences the way the receptor transmits signals through the cell membrane.

Until now, understanding of GPCR structure has been based largely on the crystal structures of the inactive state of rhodopsin, a type of GPCR. Rhodopsin is more easily obtained and also a remarkably stable GPCR, retaining its function under laboratory conditions that denature other GPCRs.

Trying to determine the structure of GPCRs in order to see how they react to hormones and neurotransmitters has been hindered by their low natural abundance and the instability of these proteins in the laboratory. But now Dr Schertler, in collaboration with Dr Daniel Oprian from Brandeise University in Boston, Massachusetts, has been able to stabilise and crystallise recombinant rhodopsin and finally obtain the first structure of a recombinant GPCR using high brilliance microcrystallography.

Using the latest techniques in protein expression crystallisation and micro-crystallography, Dr Schertler in collaboration with Dr Brian Kobilkas' team from Stanford has now obtained a high-definition crystal structure of the unmodified human beta 2 adrenoceptor, a receptor for adrenaline that plays important roles in cardiovascular and pulmonary physiology. This is the first non-rhodopsin, pharmacologically-relevant GPCR to have its structure determined at an atomic level. The breakthrough came when the team of scientists used a monoclonal antibody fragment to create a more stable ‘receptor antibody complex', in which the G protein binding site of the receptor could be clearly defined. This success is the end of a very long quest for the structure of an adrenergic receptor and the beginning of a truly molecular pharmacology of GPCRs.