ESRF helps unveiling an important receptor protein structure that will aid development of new drugs

14-11-2007

Many of the drugs on the market today directly act on the cells in the body that catalyse recovery from illness. Steering the cell’s behaviour is performed by molecules present in the cell membrane, that relay messages from the outside into the cell. The drug merely stimulates or inhibits these receptor molecules to signal into the cell’s interior. Since more than a decade, though, all of the roughly 700 known receptor molecules in the human body, called G protein-coupled receptors (GPCRs), have resisted the combined efforts by scientists to unravel their three-dimensional structure. An international group from the Medical Research Council (UK), in cooperation with Stanford University (USA) and the ESRF (European Synchrotron Radiation Facility) have now succeeded to obtain the first clear images of a human GPCR. The group used the latest laboratory techniques including high brilliance microcrystallography at the ESRF European light source, to overcome two main difficulties: GPCRs are only available in minute quantities and they are instable under laboratory conditions.

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Learning more about the structure of the GPCRs and how they transmit signals over the cell membrane will help new drug development. Medical scientists can develop small molecules for therapeutic effects more rapidly and increase the selectivity of drugs to reduce the negative side effects of new medications.

The unveiled molecule is a receptor for adrenaline that plays important roles in pulmonary and cardiovascular physiology; for example, it is essential in determining the speed of the heart beat. “This newly identified structure will be used as a model for other receptor molecules and will contribute in a wide range of drug discovery programmes”, asserts Gebhard Schertler, researcher from Medical Research Council (UK).

gpcr

Crystal structure of human b2 adrenergic receptor in complex with an antibody fragment solved using microcrystallography. Credits: G. Schertler.

“Since Schertler’s first experiments at the ESRF some ten years ago, our microfocus beamline has been steadily improved along the evolving user needs. At the same time, the first dedicated ESRF protein beamline for microdiffraction ID23-2 was created. Without all this, it would have been impossible to achieve the GPCR structures”, explains Christian Riekel, scientist in charge of the ID13 microfocus beamline at the ESRF. He adds: “Research such as this one represent an excellent starting point for the ESRF future upgrade, which will take the boundaries of science even further.”


References:

Rasmussen et al., Crystal structure of the human ß2 adrenergic G-protein-coupled receptor,. Nature. doi:10.1038/nature06325

Previous papers leading up to this work and alluded to in the text:
Standfuss et al., Crystal structure of a thermally stable rhodopsin mutant, Journal of Molecular Biology.  doi: 10.1016/j.jmb.2007.03.007
Riekel et al, Protein crystallography microdiffraction, Current Opinion in Structural Biology. doi: 10.1016/j.sbi.2005.08.013