B.Sc. Honors (Physics), University of Edinburgh, 1965;
Ph.D. (Protein Crystallography), University of Cambridge, 1970
Our research concentrates in two areas: on the application of synchrotron radiation techniques to dynamic X-ray diffraction studies of macromolecules; and on the structures, mechanism and design of natural and engineered photoreceptors.
With the advent of extremely intense, polychromatic, pulsed synchrotron X-ray sources, the X-ray exposure times required to record an excellent X-ray diffraction pattern have dropped dramatically to the microsecond time range and, in special cases, to 100 picoseconds. That is, exposure times are now comparable with the lifetime of biochemical intermediates in such fundamental processes as enzyme catalysis, ligand-binding and release, and photocycling in light-sensitive systems. The question then arises: Can we generate such intermediates in the crystal and follow the evolution of their tertiary structures as the reaction proceeds, through observation of changes in the X-ray diffraction intensities? The short answer is "yes".
However, ultrafast reaction initiation in the crystal is accomplished by a brief, intense laser pulse, which of course requires that the molecules be light-sensitive. We therefore began our studies on signaling photoreceptors of various classes. These reveal general principles e.g. that light sensor (input) and effector (output) functions are contained on different protein domains; and signaling photoreceptors appear to have evolved by domain fusion. Since not all interesting biological systems are light-sensitive we then asked: can we apply these general principles to confer sensitivity to light on othertwise light-insensitive systems, such as transcription factors or enzymes such as histidine kinases? Again the short answer is "yes".
This leads to the development of powerful new tools for cell biology and biophysics, and extends the reach of optogenetics beyond natural photoreceptors such as channelrhodopsin to engineered photoreceptors, and beyond the neurosciences.