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John F. RYAN || 28 October || Visionary Symposium on Nano-Bio-Cogno

Probing receptor structure and function at the single molecule level

Abstract

Nanoscale measurement techniques have many potential applications in biology and medicine, ranging from molecular diagnostics and early stage detection of disease to targeted drug delivery. These techniques have the ability to image and manipulate individual molecules and to measure molecular interactions in real time with sub-molecular resolution. In this talk I will describe recent progress in using atomic force microscopy (AFM) to measure membrane proteins. In many respects these molecules are the basic information processing devices in biology: they are responsible for sensory signal input and transduction, and they control and regulate processes via nanoscale mechanical motion. They include: ion channels that allow specific ions to permeate the cell membrane and so control the trans-membrane voltage; numerous receptors that respond to small molecules, such as hormones and amino acids, thereby transmitting signals to cells and modulating their behaviour. Their immense importance is indicated by the facts that up to 30% of all genes code for membrane proteins, and that they represent 60% all drug targets. I will describe AFM measurements of:
A. the prototypical potassium ion channel KcsA, and pH-dependent changes related to gating,
B. neuroreceptors such as AMPA receptors, which are involved in the processes of memory and learning, and
C. photoreceptors involved in the process of energy transduction, e.g. bacteriorhodopsin (bR), a light-driven proton pump.

While recent advances in x-ray crystallography and nuclear magnetic resonance have greatly improved our understanding of membrane protein structure, the new AFM techniques permit real-time imaging of the protein function with few-Å resolution in a physiological environment. Arguably the most exciting breakthrough in this field is the development of high-speed AFM which is able to provide sub-molecular imaging with few-ms time resolution. Using bR as the model system I will present real-time measurements of light-induced structural changes that occur during the receptor photocycle. These measurements open up the possibility of direct measurements of ligand binding and drug-receptor interactions.

John F. Ryan, Clarendon Laboratory, University of Oxford