Scientific Tour de Force Signals Major Step for Structural Biology

Posted on: 27 July 2015

In a major step for structural biology, a multi-institution scientific ‘tour de force’ has produced the first structural blueprint of a complex between ‘rhodopsin’, the light sensing protein in the retina, and one of its cellular signalling partners, ‘arrestin’.

The blueprint provides one of the first convincing examples of the need for an X-ray-free electron laser technique (serial femtosecond crystallography), which provides precise molecular structural information by analysing tiny protein crystals. A more traditional method, which relies on synchrotron X-rays, was unsuccessful at providing the required blueprint.

Rhodopsin is a pigment-powered protein that is extremely sensitive to light and enables us to see in low light conditions. It is a G-protein coupled receptor (GCPR), which makes it a member of the largest family of cell-surface receptors in the body.

Recent advances in structural biology have pointed to specific signalling pathways dictating the way GCPR’s like rhodopsin operate. This makes them of huge interest to drug developers, who hope to design drugs that selectively target unique elements of these specific pathways. Around one third of all currently used drugs target GCPR’s.

If new drugs can be designed to work solely on their specific targets, patients receiving treatment should be considerably less likely to experience side effects, and the drugs themselves may also be more effective.

This is the chief reason why the new technique for determining protein structure is so exciting: as scientists characterise more and more GCPR-signalling partner liaisons, their resultant blueprints could effectively become pharmaceutical battle plans that can be used to target a suite of unique proteins for therapeutic purposes.

Professor of Membrane Structural and Functional Biology in the School of Biochemistry and Immunology at Trinity College Dublin, Martin Caffrey, and members of his research group, Dianfan Li and Nicole Howe, were collaborators whose ground-breaking work has just been reported in the leading international journal Nature.

Professor Caffrey said: “This really was a tour de force. As an accomplishment, it is up there with the effort that saw Brian Kobilka characterise the ‘b2-adrenoreceptor-G protein complex’, in part for which he received his share in the 2012 Nobel Prize in Chemistry.” 

“The blueprint structure that this method produced has been backed up by complementary electron microscopy and extensive biophysical and biochemical measurements, and provides us with a molecular basis for explaining GPCR-mediated arrestin-biased signalling.”