Project summary: The MacCHESS Synchrotron Source for Structural Biology facilitates the utilization of both established and emerging technologies to advance biomedical research goals. Work performed at MacCHESS is expected to yield fundamentally important insights into biology and biomedicine, adding to the understanding of complex membrane receptor-signaling systems, the regulation of ion channels in neuronal function, catalytic mechanisms of enzymes, and the complex macromolecular assemblies responsible for gene expression. Upgrades to CHESS, including improvements to the storage ring and newly designed beamlines that will provide state-of-the-art facilities, will be in place by June 2019. MacCHESS will continue to support more than 100 investigator projects, funded by NIH and other government institutions, through two major Technology Operations Cores. These are: 1) Facility for Flexible Crystallography. The Flexible Crystallography Technology Core will take advantage of unique MacCHESS capabilities to enable the development of new X-ray techniques that may be used to broaden knowledge of biological processes. Examples include continued development of methods for serial crystallography, improvements in crystal handling techniques, the application of high pressure to crystals, and analysis of macromolecular motions through the study of X-ray diffuse scattering. A high level of support for more routine macromolecular crystallography will also be provided, to answer a range of structural questions involving single proteins, nucleic acids, and macromolecular complexes, as well as to provide valuable complementary information to the results obtained from the less standard types of structural studies. 2) Facility for Biological Small Angle X-ray Scattering (BioSAXS). This technology core will implement state-of-the-art hardware, software, and expertise to support the increasingly in- demand BioSAXS technique. In addition to determining the shapes of proteins, nucleic acids, and larger assemblies in solution, BioSAXS allows researchers to obtain information regarding global conformational changes within macromolecular complexes (e.g. growth factor receptors, RNA-splicing complexes) and/or the changes in their oligomeric states that have important functional consequences. This core will also provide the necessary equipment and expertise for investigators interested in performing time-resolved BioSAXS or BioSAXS studies conducted under high pressure. MacCHESS will provide a strong Administration Core to support these activities and will continue to educate users, and the biomedical research community, through a Training and Outreach Core. Collectively, these efforts will offer unique opportunities to our users for pursuing some of the most challenging questions in structural biology and for obtaining structure-function information that will ultimately highlight novel therapeutic targets and aid in the development of clinical strategies for dealing with disease.

Project narrative: High-resolution structural information is essential for understanding the molecular basis of a number of diseases. Among the important requirements for obtaining such information are (1) the routinely available capability to study the conformation and oligomeric states of biomedically relevant proteins and protein complexes both in crystals and in solution, including methods for handling the poorly-diffracting crystals often generated by membrane-receptors, ion channels, and signaling proteins, and (2) the means to continue to improve on the available techniques, extending our knowledge of complex systems which are not now understood. MacCHESS will provide the necessary facilities and technology to generate structure- function information of great interest to the biomedical community.