Working together, two scientific organizations have achieved a key milestone earlier than planned: using X-ray crystallography and nuclear magnetic resonance to probe at the atomic level, they have determined the structure of 1,000 proteins from more than 40 organisms that cause deadly diseases in humans, such as leprosy, TB, cholera, anthrax, the plague, salmonellosis, amoebic dysentery and influenza. The knowledge gained should help improve disease diagnosis and the discovery of new drugs.
A joint statement released last week says teams of scientists from the Center for Structural Genomics of Infectious Diseases (CSGID) and the Seattle Structural Genomics Center for Infectious Disease (SSGCID) have been working toward this goal since 2007. The teams now comprise a total of 200 scientists.
Their work is funded by five-year contracts from the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health (NIH) in the US.
Dr. Wayne Anderson, Professor in Molecular Pharmacology and Biological Chemistry at the Northwestern University Feinberg School of Medicine in Chicago, heads the CSGID, an international consortium that includes research centres from the US, the UK and Canada. He told the media that:
“Determining protein structures can help researchers find potential targets for new drugs, essential enzymes, and possible vaccine candidates.”
Heading up the SSGCID is Dr. Peter J Myler of the Seattle Biomedical Research Institute (Seattle BioMed), and Global Health Research Professor in the Department of Medical Education and Biomedical Informatics at the University of Washington in Seattle. He said:
“The importance of this work is highlighted by the 80+ scientific articles published by the two centers, which also showcase new methodologies developed by each center.”
The teams selected the proteins according to their biomedical relevance, plus their potential to help improve treatment and diagnosis. A third of them were direct requests from researchers working on infectious disease.
The process starts with selecting target proteins using bioinformatics, then cloning their genes into bacteria to produce, purify and crystallize the proteins. After that they are sent to 9 different centers in the US and Canada for X-Ray diffraction.
Anderson said they are “laying the groundwork” for drug discovery.
The work is especially important as more and more disease-causing bacteria become increasingly resistant to current drugs. The superbug MRSA (methicillin-resistant Staphylococcus aureus) for instance is now resistant to antibiotics like penicillin and cephalosporins.
The bacterium that causes TB (mycobacterium tuberculosis) also has multi-drug resistant strains (MDR-TB). This is a growing global health problem that has become more serious because of recent cases of extensively drug resistant strain (XDR-TB) from India.
The World Health Organization (WHO) and other global agencies have called for scientific communities to work together to find new and better drugs to fight TB and the resistant strains in particular.
One approach is to change the current drugs so the bacteria don’t recognize them: that would make the drugs powerful once more. To do this scientists need more information about the three-dimensional structure of the proteins that the drugs target. Seeing how the atoms are arranged in space and how they interact with one another is valuable to researchers trying to work out how the bacteria develop resistance.
The teams have solved 22 M. tuberculosis protein structures, and another 126 structures from other Mycobacterium species. These other species cause disease such as leprosy, Buruli ulcer, and lung infections in AIDS patients.
When the two teams got their first NIH funding in 2007, they thought they could determine 750 structures in 5 years: but the desperate need for data has driven them to exceed this target and reach 1,000.
One reason for their success is the greater speed and efficiency of the technology, as Anderson explained:
“It used to take four years to determine one structure, now we can do about three per week.”
Once a protein structure is solved, the scientists put the data in the NIH-supported Protein Data bank, which other scientists can access for free. The structures can also be accessed on the CSGID and SSGCID websites. Scientists can also fill in forms on these sites to propose new protein targets.
Plus, the two centers also freely distribute the protein expression clones via the NIH-funded Biodefense and Emerging Infections Research Resources Repository.
Written by Catharine Paddock PhD