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CSGID Determines the Structures of 100 Proteins

Investigators at the Center for Structural Genomics of Infectious Diseases (CSGID) determined their 100th pathogen protein structure since beginning in 2007. It was deposited into the Protein Data Bank (PDB) on Aug. 5.

Led by Wayne Anderson, molecular pharmacology and biological chemistry, researchers at the CSGID use x-ray crystallography to examine the atomic details of proteins from major human pathogens, including those responsible for anthrax, plague, and cholera. By determining the protein structures, scientists are able to pursue drug discovery, improved diagnostics, and vaccine development.

The Center — a multi-institutional, international consortium funded by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health — works on proteins requested by investigators who need structural information to advance their research. Placing the structural results into the PDB international database makes the results publically available to the entire scientific community and creates opportunities for cross-disciplinary collaboration.

The CSGID is a consortium of eight different laboratories (six in the US, one in Canada and one in the United Kingdom) that has been funded by NIAID with the goal of applying structural genomics approaches to potential drug targets from NIAID category A, B, and C priority pathogens. During the coming three years, the CSGID expects to determine approximately 100 protein structures per year, a feat that has only recently become possible thanks to improved techniques.  During the past 10 years the investigators that make up the CSGID have led efforts to develop and apply high-throughput structural biology methods. Each institution of the consortium contributes to different aspects of the high-throughput CSGID pipeline, which include selecting proteins for study, cloning the genes coding for those proteins, protein production, purification and crystallization, data collection at the synchrotron (Advanced Photon Source at Argonne National Laboratory), and structure determination.

The 100 protein structures completed thus far represent a selection of proteins with biomedical relevance and potential therapeutic benefits.  Proteins that are studied include potential targets for new drugs, essential enzymes, proteins that contribute to the virulence of the pathogens or are involved in drug resistance and possible vaccine candidates.

Most of the structures that have been determined so far by CSGID are from Salmonella enterica, Vibrio cholerae (including the very first structure determined by CSGID of a protein target requested by the scientific community – see figure), Yersinia pestis, Staphylococcus aureus and Bacillus anthracis.

A major focus of CSGID is to determine the structures of complexes of the target proteins with small molecule compounds such as natural substrates, cofactors and drug candidates, for drug discovery purposes.  In addition to structure determination, CSGID provides the scientific community with the protein expression systems deposited in the Biodefense and Emerging Infections Research Resources Repository, BEI Resources.

CSGID has been funded with Federal funds from the National Institute of Allergy and Infectious Diseases under Contract No. HHSN272200700058C. For more information, please contact Dr. Elisabetta Sabini, CSGID project manager, at (312) 503-6973 or e-sabini@northwestern.edu.

The principal investigators of the CSGID consortium. From right to left: Wladek Minor, University of Virginia; Andrzej Joachimiak, Argonne National Laboratories/University of Chicago; Christine Orengo, University College London; Wayne Anderson, Northwestern University; Zbyszek Otwinowski, University of Texas Southwestern Medical Center; Daved Fremont, Washington University; Alexei Savchenko, University of Toronto; and, in the insert, Aled Edwards, University of Toronto.
Crystal structure of the cysteine protease domain (CPD) from Vibrio Cholerae RtxA toxin responsible for cholera pandemics. The Vibrio cholerae RtxA is a 4545 residue member of the Multifunctional Autoprocessing Repeats in Toxin family. CSGID has determined the structure of CPD in complex with its ligand inositol hexakisphosphate, which is required for activity. The determination of this structure was requested by Karla Satchell of Northwestern University. Anyone can submit requests to CSGID by clicking here. The 100th structure was a protein produced by Bacillus anthracis that is thought to be a major part of anthrax's resistance mechanism to aminoglycoside family of antibiotics.

 

 

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