Study Weekend Program... UP


The Uppsala Electron Density Server - Where seeing is believing ...

Gerard Kleywegt
Uppsala University
Sweden

With the explosive growth of the number of experimentally determined macromolecular structures, "structural awareness" is becoming an important aspect of many disciplines, ranging from medicinal chemistry to cell biology. This means that many scientists who have not been specifically trained in the area want to make use of structural information in order to explain the molecular basis of their own research findings, to plan new experiments, to design novel ligands, substrates or inhibitors, etc. What these users of structural information often are unaware of is that there are limitations to and uncertainties in the experimentally determined structures. A number of protein structures have been published (often in prestigious journals) that turned out to be partly or entirely incorrect. A few examples will be given, and simple ways in which non-experts can assess the overall reliability of structures will be discussed.

However, as technology improves, such gross errors are less and less likely to occur. On the other hand, mistakes in the details of the structures are much easier to make, and concomitantly more difficult to detect. It is often in these details, however, that the value of a structure lies, since they reveal the molecular basis of interactions. This is particularly true for non-macromolecular entities (ligands, inhibitors, substrate-analogues, sugars, ions, etc.). Some of the pitfalls and limitations of the use of structural information will be discussed, with a view to structure-based design.

To properly assess the results (and reliability) of a crystal structure determination requires access to the experimental electron density. Our efforts to provide such maps, and information derived from them, for all crystal structures for which structure factors have been deposited with the PDB will be discussed. They have resulted in EDS - the Uppsala Electron Density Server (http://fsrv1.bmc.uu.se/eds). Some of the technical details of the EDS implementation will be discussed, and some initial statistics and analyses presented. Finally, the structure factor deposition track records of the major journals will be highlighted.