Cambridge Institute for Medical Research

Professor Randy Read

Home | Research Profile | Key Publications

Protein crystallography and pathogenesis

Research in my group is in the field of protein crystallography. Crystallography is the primary method for determining the three-dimensional structure of a protein, which provides an essential framework for a detailed understanding of its biochemistry. We work both on extending the scope and power of the methods used in protein crystallography, and on applying those methods to determine new protein structures. In choosing what to study we focus on proteins involved in pathogenesis and disease, the structures of which can be exploited in the development of new therapies.

One focus of recent structural work has been on members of the serpin family, most of which undergo an extraordinary conformational change on cleavage by proteases. The structures of two hormone-binding globulins show how they harness this conformational change to deliver thyroxine and cortisol to their sites of action. Our work on angiotensinogen, the source of the hormone angiotensin, has shed new light on how blood pressure is modulated. We also have an interest in enzymes mutated in inherited metabolic diseases. The structure of galactocerebrosidase is helping to understand how mutations in this enzyme lead to Krabbe disease.

In crystallographic theory, we focus on the understanding of probability distributions relating the structure factors that arise from the diffraction experiment. A detailed understanding of these probability distributions underlies new developments in maximum likelihood methods, which we are implementing in our program Phaser. The current version of Phaser can solve structures by molecular replacement (i.e. using the known structures of related proteins), by using the information from single-wavelength anomalous diffraction (SAD), and by a combination of the two. In a collaboration with the developers of the modelling program Rosetta, we have been excited to find that the combination of molecular replacement and advanced modelling can solve structures that elude previous methods.

Funding

• Wellcome Trust
• National Institutes of Health
• British Heart Foundation

Group Members