Robert Ford

Mysteries of membranes

Our research centres on the understanding of the structure of a class of proteins that are found in biological membranes. We have studied a variety of different proteins. The most recent developments in our research have involved the application of new methodology for cryo-electron microscopy of in-situ crystalline arrays to large membrane protein complexes. These have been used to obtain medium resolution structures for this class of proteins.  Over the past 10years our research interests have extended to membrane proteins that are involved in pumping drugs out of cells (multi-drug resistance proteins). Lack of high quality crystals at first necessitated the analysis of these membrane proteins by single particle alignment and averaging, and this has led us to the first 3D structure for this type of transporter. We now have produced large 2-D crystals of this protein, opening up a route for the elucidation of the structure of the protein at much higher resolution. A structure at 0.8 nm resolution was published in 2005, and we now have a structure for a separate multi-drug transporter at higher resolution. These projects involve several biochemical and biophysical approaches.

Figure 1. The images show different views of a single membrane protein, P-glycoprotein. This is a membrane protein that is crucial in the development of resistance in cancer cells treated by chemotherapy. When levels of this protein reach sufficient levels, the chemotherapeutic drugs are actively transported out of the cancer cells, and the cancer can progress and kill the patient. We need to know more about the protein’s structure to try to prevent this happening. Note the large pore in the centre of the structure that we think is involved in allowing the movement of the chemotherapy drugs out of the cell. The molecule is about 8nm in diameter.