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| About Gerard Kleywegt (University of Uppsala) |
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Gerard J. Kleywegt obtained a degree in chemistry from the University of Leiden (The Netherlands) in 1986, and his doctorate from the University of Utrecht (The Netherlands) in 1991. His PhD thesis (supervised by Rob Kaptein and Rolf Boelens) was concerned with the automation of the interpretation of homonuclear two-dimensional and three-dimensional NMR spectra of proteins. After a short period of work for a commercial software company from California, he moved to Sweden to join T. Alwyn Jones' protein crystallography laboratory in Uppsala, for what was supposed to be a one-year post-doc. Fifteen years later, he is working as an independent investigator at Uppsala University. He has been the coordinator (and subsequently programme director) of the Swedish Structural Biology Network (SBNet) since its inception in 1994. In 2001, he was awarded a five-year Research Fellowship by the Royal Swedish Academy of Sciences. His research interests include protein crystallographic methods development, protein structure validation, structural bioinformatics and, more recently, chemoinformatics. Eventually, though, he hopes to make a career in moose farming.
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Protein crystallography: not as simple as ABC then?
Gerard J Kleywegt, Uppsala University, Uppsala, Sweden
The recent debacle with the ABC transporter structures has shown (not for the first time, unfortunately - and probably not for the last time either) that the mere fact that a pretty crystal structure is reported in the pages of a glossy journal does not guarantee that the structure is even close to being correct. Some of the causes of serious errors in biomacromolecular crystal structures will be discussed. In addition, a few examples of such errors will be given, and simple ways in which non-experts can assess the overall reliability of a protein crystal structure will be discussed. However, even when the overall structure is reliable, this is not necessarily true for each and every detail. Particularly relevant in this respect are the protein residues that interact with substrates or inhibitors and the interacting molecules themselves. A few examples will be used to demonstrate that the structures of ligands etc. are often less reliable than those of their proteinaceous hosts.
Obviously, for users of protein structures these observations have important implications. First and foremost, crystal structures should be treated with healthy scepticism rather than reverence. The best way to assess the reliability of critical aspects of a structure (ligands, active-site residues, metal-binding sites, interface residues, etc.) is to inspect the experimental electron density maps. Our efforts to provide such maps, and information derived from them, for all crystal structures for which structure factors have been deposited with the wwPDB will be discussed. They have resulted in EDS - the Uppsala Electron Density Server (http://eds.bmc.uu.se/).
References:
- GJ Kleywegt, "Validation of protein crystal structures", Acta Cryst., D56, 249-265 (2000).
- AM Davis, SJ Teague & GJ Kleywegt, "Applications and limitations of X-ray crystallographic data in structure-based ligand and drug design", Angew. Chem. Int. Ed., 42, 2718-2736 (2003).
- GJ Kleywegt, MR Harris, J Zou, TC Taylor, A Wählby & TA Jones, "The Uppsala Electron-Density Server", Acta Cryst., D60, 2240-2249 (2004).
- GJ Kleywegt, "Crystallographic refinement of ligand complexes", Acta Cryst., D63, 94-100 (2007).
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