23 Nov 2017

Crystallographers identify 1,000 protein structures

The Canadian Light Source is celebrating two milestones reached by scientists who have conducted research at the national facility at the University of Saskatchewan.

PDB ID: 6B0S

Scientists have solved 1,000 protein structures using data collected at CLS’s CMCF beamlines. These have been added to the Protein Data Bank – a collection of structures solved by researchers globally. Researchers have also published 500 scientific papers based on their work using the crystallography beamlines.

Proteins are the building blocks of life and are described as the body’s workhorses. The body is made of trillions of cells. Cells produce proteins, which do the work of breaking down food, sending messages to other cells, and fighting bacteria, viruses and parasites. The discoveries at the CLS range from how the malaria parasite invades red blood cells to why superbugs are resistant to certain antibiotics and how parkin protein mutations result in some types of Parkinson’s disease. Understanding how these and other such proteins work can potentially save millions of lives.

“Each of these protein structures that have been solved at the CLS represents a significant contribution to the global body of knowledge in the areas of biology and biochemistry, advancing health research,” says CEO Rob Lamb.

“We are proud of these milestones, and the hard work and dedication that went into achieving them. Scientists come from all over Canada and around the world to use our state-of-the-art facility supported by fantastic staff scientists.”

Using powerful synchrotron X-ray light, scientists explore human, animal, plant, bacterial, viral and parasitic proteins as well as nucleic acids. After exposing a protein crystal to synchrotron light, the scientists are able to use the information to produce a 3-D model that shows the positions of the atoms. This structural information provides details about how proteins function and interact. Scientists then use this information to better understand biology, environmental processes, as well as human health and disease. Often, they use the information to develop new pharmaceuticals.

Miroslaw Cygler

“These beamlines are a huge boost to the Canadian structural biological community,” says Miroslaw Cygler, University of Saskatchewan professor of biochemistry and Canada Research Chair in Molecular Medicine Using Synchrotron Light. He is also the leader of the CMCF beamline advisory team.

“Every protein crystallography lab in Canada from coast to coast to coast uses this facility to do experiments. Canada is a big country. Travelling is very expensive. From the very beginning, one of the missions of the facility was to provide remote service. This is really crucial in both impact and importance to Canadians,” says Cygler.

Jean-Philippe Julien

Jean-Philippe Julien couldn’t agree more. Julien is the Canada Research Chair in Structural Immunology and a scientist in Molecular Medicine at The Hospital for Sick Children Research Institute, as well as an assistant professor in the departments of biochemistry and immunology at the University of Toronto.

In the past two years, he has solved 20 protein structures using remote data collection. He sends crystal samples to Saskatoon where CLS scientists assist by mounting the samples on the beamline and then Julien’s team operates the equipment from their lab in Toronto. Structure 6B0S (crystal structure of circumsporozoite protein aTSR domain in complex with 1710 antibody) is the one-thousandth protein structure solved at the CLS and is part of Julien’s research into developing a vaccine that prevents the malaria parasite from causing infections.

The World Health Organization reports that nearly half of the world’s population is at risk of contracting malaria, with hundreds of thousands of children dying every year.

In collaboration with scientists in Germany, Julien’s team examined B cells – a type of white blood cell – from volunteers who received a candidate malaria vaccine and were then exposed to the malaria parasite to evaluate protection in a clinical trial. By solving the protein structure of an antibody developed by one of the European volunteers in this study, Julien has learned more about how the vaccine interacted with their immune system. This provides scientists with further clues as to how to alter the vaccine to improve immunity to malaria.

“In characterizing human antibody responses to malaria antigens, it is critical to have access to a world-class synchrotron beamline within Canada,” says Julien.

“Recent upgrades to CMCF have tremendously increased the sensitivity and throughput of data collection, enabling us to solve more antigen-antibody structures informing our quest towards the design of improved malaria vaccine candidates.”

Julien’s research describing this latest protein structure was published this week in The Journal of Experimental Medicine.

More than 70 academic, government and industrial research groups from across Canada and the United States conduct research using the CMCF beamlines.

The number of depositions has been increasing every year and with upcoming upgrades on the beamlines, the volume of work is expected to continue to accelerate.

The 500th paper was the result of research by Cygler’s laboratory at the U of S. Using crystallography as well as other techniques, the researchers have a better understanding of how iron-sulfur clusters are synthesized in the body. These clusters are key components of many proteins critical to life and defects in the formation of the clusters can cause severe neurological and metabolic diseases, often with fatal outcomes. The findings were published in Nature Communications.

The 500 scientific papers stemming from research conducted at the CLS have appeared in some of the world’s top scientific journals, including The New England Journal of Medicine, NatureScience, and Cell.

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Crystal structure of circumsporozoite protein aTSR domain in complex with 1710 antibody (6B0S). DOI: 10.2210/pdb6b0s/pdb

Scally, Stephen W., Rajagopal Murugan, Alexandre Bosch, Gianna Triller, Giulia Costa, Benjamin Mordmu?ller, Peter G. Kremsner, B. Kim Lee Sim, Stephen L. Hoffman, Elena A. Levashina, Hedda Wardemann, and Jean-Philippe Julien. “Rare PfCSP C-terminal antibodies induced by live sporozoite vaccination are ineffective against malaria infection.” Journal of Experimental Medicine (2017). DOI: 10.1084/jem.20170869

Boniecki, Michal T., Sven A. Freibert, Ulrich Mühlenhoff, Roland Lill, and Miroslaw Cygler. "Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex." Nature Communications 8, no. 1 (2017): 1287. DOI: 10.1038/s41467-017-01497-1

The Canadian Light Source is a national research facility, producing the brightest light in Canada—millions of times brighter than even the sun. One of the largest science projects in our country’s history, more than 1,000 scientists from around the world use our light every year to conduct ground-breaking health, agricultural, environmental and advanced materials research.

The Canada Foundation for Innovation, Natural Sciences and Engineering Research Council, National Research Council of Canada, Canadian Institutes of Health Research, the Government of Saskatchewan and the University of Saskatchewan fund the CLS operations.

The CMCF beamline advisory team, working closely with the CLS, supports the funding and operation of the CMCF beamlines. Current members include Mirek Cygler, University of Saskatchewan (team leader); Natalie Strynadka, University of British Columbia; Albert Berghuis, McGill University; Michel Fodje, CLS; Marie Fraser, University of Calgary; Mark Glover, University of Alberta; Pawel Grochulski, CLS and U of S; Brian Mark, University of Manitoba; Stanley Moore, U of S; Emil Pai, University of Toronto; James Rini, U of T; Joe Schrag, National Research Council; Filip Van Petegem, UBC.

More science highlights from CMCF

Combatting malaria

According to the World Health Organization, one child dies from malaria every minute. New methods to combat malaria parasites are particularly important as these parasites continue to develop resistance to front-line drugs. A different strategy for stopping malaria infections is targeting a potential Achilles’s heel of malaria infection: the unique strategy it uses to enter a human red blood cell. Research from a team at University of Victoria has contributed to a high resolution model of how malaria invades red blood cells. Similar to a magician pushing a pin into a balloon without popping it, the malaria parasite stealthily slips itself into human cells. Understanding this mechanism opens up a new way to stop malaria in its tracks.
DOI: 10.1126/science.1204988

Towards a bacterial meningitis vaccine

Approximately 15 to 20 per cent of adolescents and young adults in Canada carry meningococci bacteria, the leading cause of bacterial meningitis. As a defense mechanism against the bacteria, the immune system of mammals use a form of nutritional immunity by cutting off access to zinc and preventing their colonization. Zinc plays an essential role in biological processes and thus has an important role in disease. Gram-negative bacteria, such as those that cause meningitis, produce a protein called ZnuD to uptake zinc more efficiently and overcome the host’s defense mechanism. Researchers from the University of Toronto and the Hospital for Sick Children identified and mapped the structure of three zinc-binding protein intermediates, providing a framework for the rational design of a ZnuD based vaccine.
DOI: 10.1038/ncomms8996

Protecting fisheries from disease

The infectious salmon anemia virus (ISAV) has caused billions of dollars in financial losses in several countries over the last three decades. Knowing how and where the protein attaches itself is a key piece of information for vaccine developers to develop an antigen that will prevent the attachment process. Outbreaks of the devastating virus have periodically decimated farmed salmon operations in Canada’s East Coast, Chile, Scotland and Norway, and the virus has been found in wild salmon stocks as well. Despite its name, the virus is not isolated to salmon. Rainbow trout are also susceptible. Research led by University of Toronto researchers provided a better understanding of how the virus attaches to cells and infects the fish. DOI:10.1073/pnas.1617993114

Outsmarting superbugs

Macrolide antibiotics are the fourth largest class of antibiotics and are prescribed for a variety of infectious diseases, including upper respiratory tract, skin and soft tissue infections. Erythromycin and other macrolide antibiotics are also prescribed as an alternative to penicillin. Yet superbugs have developed a resistance to these antibiotics. McGill University researchers determined that enzymes in the bacteria have the ability to chemically modify antibiotics. The enzymes take a molecule that has a phosphate group in it and they stick that phosphate group on to something else. That little change is just enough to make a compound no longer an antibiotic. When that happens, it becomes a useless compound.
DOI: 10.1016/j.str.2017.03.007

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