Table Of Contents

Professor Ford's Website

Manchester Interdisciplinary Biocentre, Manchester, England

Guelph University, Canada

What is structural biology?:

Structural biology is a rapidly developing area of biology that is aimed at determining the three-dimensional structures of biologically-important molecules such as proteins, DNA and RNA. Structural biology developed as a field alongside molecular biology in the 1950s and 1960s and almost everyone knows some of the pioneers in this field – Hodgkin, Wilkins Watson, Crick who determined the structure of DNA. Less widely known are the pioneers of protein structure determination – Kendrew and Perutz. Because of its dependence on physics and complex technology, structural biology is still widely perceived as being daunting for the non-expert. However developments in computer software and instrumentation mean that structural biology is now expanding to become available to any laboratory and soon structure determination for some proteins will be a routine operation.

How will this happen?

Firstly, technical developments in biochemistry and X-ray crystallography are making routine structure determination for proteins much more feasible. The introduction of kits for protein production and purification and similar kits for crystallisation screening allow any biology lab with even limited resources to generate crystals of recombinant proteins. At the same time, in-house X-ray generators and detectors are becoming (relatively) cheaper, hence any reasonably resourced biology division should consider purchasing such a source (a decent set-up can be purchased for much less than a confocal microscope). Perhaps the most spectacular advance has been in crystallography software that allows moderately experienced operators to progress from X-ray data collection to atomic co-ordinate deposition with relatively few button strokes at a workstation.

Structural proteomics:

Another driver of progress is structural proteomics, where the goal is high-throughput protein structure determination via NMR or X-ray crystallography. It is possible that a high percentage (>95%) of the possible ways that one class of proteins can fold up in three dimensions that exist in nature will be determined over the next 10 years by the various structural proteomics consortia around the world. If a water-soluble protein’s ‘fold’ in 3D can be classified from a list, then with modelling and molecular dynamics simulations it should be possible to arrive at relatively robust 3D models of almost any soluble protein.

The future of structural biology:

Although structural proteomics will reduce the need for direct structure determination, it will not eliminate it entirely. There are many aspects of biotechnology where very accurate atomic co-ordinates are required (e.g. in drug design), and it is possible that modelling will never achieve sufficient accuracy for this. Moreover there are whole classes of proteins – membrane proteins for instance - for which high throughput structure determination is still a distant goal. Membrane proteins contain the targets for about 50% of current drugs on the market, and hence represent a huge untapped source of potential intellectual property. Moreover there are presently so few membrane protein structures that it is impossible to judge whether they will also have a relatively limited set of folds like soluble proteins, or whether there will be a much larger number of configurations. Structural proteomics is also unlikely to have much impact on the understanding of how large macromolecular complexes function in the cell. Until recently, biochemistry has been dominated by a reductionist approach which aimed at teasing apart a system into its smallest components and then studying these isolated parts in the finest possible detail. In the era post-dating the determination of the molecular components of a cell, there has been a realisation that a more global understanding is needed within the context of understanding networks of interacting complexes. This is the ‘systems biology’ approach. In order to make progress in this area, we need to develop novel structural biology methods. Cryo-electron microscopy, which is a major tool for our laboratory, can provide a means of obtaining this information, and recent developments in tomography even allow the imaging of these complexes inside the cell itself.

Wealth generation?

Universities have a major role to play in terms of training within the area of structural biology as well as in the development of novel methodology. Most major biotechnology and pharmaceutical concerns now have their own structural biology programs that are aimed towards novel therapies and rational drug design. So far this has meant that Universities have been supplying PhDs trained in X-ray crystallography, NMR and molecular modelling who are being employed to generate structures, build homology models and to design or optimise drugs in-silico. Occasionally, University structural biology groups also provide expertise (consultancy) or provide structural data for this sector of the economy. A missing link here is cryo-electron microscopy – so far underemployed by the pharmaceutical research sector. This gap is probably due to two major factors:

(i) Lack of trained personnel: Historically, there have been very few laboratories producing trained researchers in this area. The huge expansion of the field over the last 5-10 years has therefore led to a severe shortage of cryo-electron microscopists, and almost all trained personnel have immediately been recruited into academic university posts.

(ii) Perception that atomic resolution was all-important (cryo-electron microscopy usually operates in the molecular resolution realm (4 - 30Å)): Because of the trend towards systems biology, it seems likely that the pharmaceutical sector will be following the lead of academic institutions and employing cryo-electron microscopy in their programs.