The project requests funds for purchase of a state-of-the-art, large area, fast readout, charge coupled device, X-ray area detector and detector mount, to be installed on the 14-ID-B insertion device beam line operated by BioCARS/University of Chicago at the Advanced Photon Source, Argonne National Laboratory. This beam line is the flagship of a national facility for synchrotron-based structural biology funded since 1992 by NCRR/NIH. The facility is open to all qualified scientists, and is one of the most productive beam lines at the Advanced Photon Source as judged by the number of peer- reviewed scientific papers - including those in the top journals - published annually by our BioCARS users. The facility offers world-leading capabilities in time-resolved single crystal diffraction, and in the safe examination of biohazards at the BSL3 level. BioCARS research and development has concentrated on applications in time- resolved X-ray crystallography. Our users conduct both collaborative and service research in that area and in somewhat more conventional, static crystallography. Our present seven-year-old X-ray detector has a relatively small active area and a relatively long readout time, which renders it unsuited to many user experiments. The first precludes its use at long crystal-to-detector distances, which both enhances the background and hinders the separation of diffraction spots from crystals with large unit cells;the second makes it unsuitable for recording sequential diffraction patterns in the millisecond time range, as is advantageous for following slower, often irreversible reactions in this range. The new detector requires the design, construction and installation of a fully-automated mount, to position the detector flexibly with respect to the crystal and X-ray beam. Crystals to be examined using this detector by our users include those of pathogenic viruses, some of which e.g. West Nile virus are human pathogens and others of which are animal, plant or insect pathogens. Other crystals are of more direct biomedical interest e.g. crystals of insulin converting enzymes, in which a successful structure determination may open up leads for structure-based drug design. Yet others are studied from the point of view of elucidating their molecular mechanism of action, by time-resolved or static crystallography. Again, an understanding of mechanism (and in particular, of the structures of short-lived intermediates) directly underpins drug design.
