Protein millennium: 1000 structures by XRD and NMR

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  • Published: Jun 15, 2012
  • Author: David Bradley
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thumbnail image: Protein millennium: 1000 structures by XRD and NMR

Pathogen proteins

Plague pit - Bubonic plague victims in a mass grave from 1720-1721 in Martigues, France  

An interdisciplinary study hinging on X-ray crystallography and nuclear magnetic resonance studies has examined 1000 proteins from more than 40 different human pathogens, including those responsible for plague, anthrax, salmonella, cholera, tuberculosis, leprosy, amoebic dysentery and influenza.

Researchers at the Center for Structural Genomics of Infectious Diseases (CSGID) and the Seattle Structural Genomics Center for Infectious Disease (SSGCID) marked the 1000-structure milestone in June and suggest that the data collected and interpreted will open up paths to novel pharmaceuticals, possible vaccines and other interventions for what are some of the most lethal organisms humanity must face.

Peter Myler who heads the Seattle Biomedical Research Institute (Seattle BioMed) and CSGID head Wayne Anderson of the department of Molecular Pharmacology and Biological Chemistry at the Northwestern University Feinberg School of Medicine, have five-year contracts from the National Institute of Allergy and Infectious Diseases (NIAID), a section f the National Institutes of Health (NIH) to investigate these 40 pathogens. The program has selected proteins of particular biomedical relevance in terms of their being targets for potential therapies as well as having diagnostic utility. Approximately one third of the proteins were studied in response to direct requests from scientists in various areas of the infectious disease research community.

"We are laying the groundwork for drug discovery," Anderson explains. "Determining protein structures can help researchers find potential targets for new drugs, essential enzymes, and possible vaccine candidates," adds Myler. The two centres have published more than 80 research papers offering details of the proteins as well as the technology and methods used in the research at each centre.

The researchers involved have high hopes that the ongoing work will lead to developments to address the growing problem of multiple-drug resistance in pathogenic bacteria. MRSA, once referred to the so-called superbug methicillin-resistant Staphylococcus aureus. Unfortunately, today, many medical practitioners have substituted the phrase methicillin-resistant for "multiple-resistant" because MRSA can fend off most of the chemical weapons we refer to as antibiotics. Some strains of MRSA have even evolved the capacity to defeat the last-line of defence antibiotics, such as vancomycin.

"By determining the structure of proteins targeted by these drugs, researchers can determine how the bacterium developed resistance and figure out what to change in the drug so that the bacteria will not recognize it," Anderson says. Other pathogens, such as Mycobacterium tuberculosis have also developed multiple-drug resistant strains rendering them an important global health problem. Recent cases of TB in India are widely resistant to conventional antibiotics and the World Health Organization (WHO) and other health authorities are hoping chemists and biomedical researchers can work together to devise new therapeutic agents to combat such diseases. The SSGCID has solved 22 structures from M. tuberculosis and an additional 126 closely related targets from other Mycobacterium species. Those pathogens are linked to leprosy, Buruli ulcer, and lung infections in AIDS patients.

The researchers originally anticipated obtaining structure solutions for about 750 proteins in the five years of their financial backing. However, X-ray and NMR techniques have advanced significantly in that time and they have far exceeded their original goal in less time. "It used to take four years to determine one structure," Anderson explains, "now we can do about three per week." The throughput is helped, of course, by the two hundred or so scientific collaborators working across the two centres with different groups within each selecting target proteins using bioinformatics, cloning the appropriate genes into laboratory bacteria for protein expression, purification, and crystallization. The X-ray diffraction data have been collected at nine different beamlines on facilities in the USA and Canada. All resulting coordinates are freely available to the research community and others through the NIH-backed Protein Data Bank and the structures are accessible via the CSGID and SSGCID web sites. There is also still time to nominate new proteins for investigation under this program.

Team effort

SSGCID members include: Seattle BioMed (Seattle, WA), Emerald BioStructures (Bainbridge Island, WA), University of Washington (Seattle, WA) and Pacific Northwest National Laboratory (Richland, WA). CSGID includes researchers from: Northwestern University (Chicago, IL), University of Chicago (Chicago, IL), J. Craig Venter Institute (Rockville, MD), University College London (London, UK), Sanford-Burnham Medical Research Institute (San Diego, CA), the University of Toronto (Toronto, Canada), University of Virginia (Charlottesville, VA), University of Texas Southwestern Medical Center at Dallas (Dallas, TX), and Washington University School of Medicine (St. Louis, MO).

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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