New light for science: synchrotron radiation in structural medicine Thomas L-M. Sorensen, Katherine E. McAuley, Ralf Flaig and Elizabeth M.H. Duke Macromolecular Crystallography Group, Diamond Light Source Limited, Chilton, Didcot, Oxfordshire OX11 0DE, UK Macromolecular crystallography (MX) is a powerful method for obtaining detailed three-dimensional struc- tural information about macromolecules. MX using synchrotron X-rays has contributed, significantly, to both fundamental and applied research, including the structure-based design of drugs to combat important diseases. New third-generation synchrotrons offer sub- stantial improvements in terms of quality and brightness of the X-ray beams they produce. Important classes of macromolecules, such as membrane proteins (including many receptors) and macromolecular complexes, are difficult to obtain in quantity and to crystallise, which has hampered analysis by MX. Intensely bright X-rays from the latest synchrotrons will enable the use of extremely small crystals, and should usher in a period of rapid progress in resolving these previously refractory structures. Introduction Imagine searching for clues in a darkened building with a beam of torchlight, and then finding a light switch. The entire room is suddenly illuminated, and that which was previously hidden is visible. Light itself is a potent tool in many areas of research. Our visual sense is most highly developed, and seeing helps in discovery and understand- ing. This article focuses on a particularly bright and pure form of light, the light produced by a particle accelerator known as a synchrotron. One of the main applications of synchrotron light in biology is in the field of macromolecular crystallography (MX). MX is one of the most powerful methods for obtaining detailed three-dimensional structural information about proteins and other macromolecules. It is a research field that has seen enormous advances during the past decades. These advances have stemmed from improved techniques in several areas, including advances in molecular biology and protein chemistry, for the cloning, expression, purifi- cation, and crystallisation of proteins. In addition, the techniques for collecting and processing crystallographic data as well as the visualisation of structures have been greatly improved. However, a further and important factor has been the increased brightness and the ability to tune the wavelength of the X-rays produced at synchro- trons, as opposed to those available at the laboratory. Consequently the use of MX to obtain structural informa- tion has become feasible for many projects within biology and medicine. MX comes with both a basic and applied ‘flavour’. Within the past decade, MX has improved our basic understanding of many aspects of biology: examples include how cations are moved across biomembranes through channels and pumps [1,2], and how the ribosome deciphers the genetic code and translates it into polypeptide chains [3–6]. At the same time, MX has had considerable impact on many drug discovery programs and has had an important role in the delivery of marketed drugs against at least seven enzyme targets. MX has also been a key technology in the development of drugs using a much larger number of targets, some of which have entered clinical trials. A recent review [7] identified >60 compounds that are in the clinic and curing patients where structural informa- tion about the protein target is available. This highlights the opportunity of using MX to provide valuable informa- tion about drugs and their targets. Furthermore, some 25 of these are in the top 200 by drug sales. How important structural information has been for the drug development process is hard to assess from the outside. In a pharma- ceutical company, MX is a complementary approach, contributing in concert with more traditional drug dis- covery. The development of HIV protease inhibitors in the 1990s is recognised as a classic example where the drug design was based on a structural understanding of the active site of the protease. In several cases, such as the anti-cancer drug Gleevec (imatinib) [8], the structure of the target molecule did not become available until late in the process, and instead of driving the design of the original drug, the information was used to address how to improve the drug. Structure determination is not always straightforward, and structural biology still faces challenges; however, the insights we have gained from the efforts invested so far fully justify putting further resources into developing MX. Structural information provides a framework for assisting the interpretation of functional data. It does not replace the functional investigations that lead to identifying the target of interest nor the rapid functional assays that are needed to test the efficacy of compounds. It does, however, help in the development from a lead compound to a potentially effective drug. Structure helps us to make more sense of our data; it shows where a compound can be modified with benefit and where it should not be modified. Here, we shall have a look at how synchrotrons produce bright X-rays and discuss how MX has been used to solve drug development issues. Furthermore, we shall discuss the challenges struc- tural medicine faces and how MX is an important step in the structural pipeline. Review TRENDS in Biotechnology Vol.24 No.11 Corresponding author: Sorensen, T.L. (Thomas.Sorensen@diamond.ac.uk). Available online 26 September 2006. www.sciencedirect.com 0167-7799/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2006.09.006