The unifying theme of CSB is toward understanding the relationship between the structure of macromolecules and their biological functions. The Centre brings together scientists of complementary expertise.
The CSB pursues three key research axes in the field of structural biology:
- conformational diseases,
- bacterial infections, and
- synthetic biology.
The areas covered by the CSB represent a strategic sector in full growth, which has undeniable economic benefits for Canada and the province of Quebec. For innovative research and discovery, it is crucial to create and maintain an open scientific environment with accessible state-of-the-art equipment platforms, shared expertise, and funding for student training.
Protein structure is a key player in most human diseases. Whether the target of an antibiotic, the substrate of a tyrosine kinase, or a defective product of a genetic mutation, proteins are at the heart of biology and the focus of nearly all therapeutic strategies. It is essential to know the structure of proteins to understand the causes of diseases and to develop new treatments.
Studies of many diseases, particularly those affecting the elderly, show that they result from abnormalities in protein structure and folding. These complications range from deep structural changes observed in neurodegenerative diseases such as bovine spongiform encephalopathy and Alzheimer’s disease, to more subtle effects when mutant proteins are not addressed to the right place in the cell. The latter are called “diseases of protein transport”. Diseases caused by defects in protein conformation impose an enormous burden on society.
In Quebec, it is estimated that among people of 65 years and over, 70,000 will suffer from Alzheimer’s disease and 25,000 from Parkinson’s disease. The CSB is in a privileged position to characterize and devise new therapeutic strategies for conformational diseases.
Active CSB initiatives on conformational disease include:
- Gerhard Multhaup’s work on understanding the biology of the precursor protein to amyloid formation in Alzheimer’s disease.
- Kalle Gehring and Jason Young’s work on neurodegenerative diseases associated with mitochondrial defects.
- Jason Young and Alvin Shrier’s research on folding defects in the protein “human ether-a-go-go related gene” (hERG), which is one of the causes of a rare disease known as Long QT syndrome, which can lead to arrhythmia or cardiac arrest.
- Gergely Lukacs and David Thomas’s research on the misfolding of cystic fibrosis transmembrane conductance regulator in cystic fibrosis.
Transmissible diseases, especially bacterial infections, are a resurgent health threat. Each year, infectious diseases are responsible for more than 14 million deaths worldwide (one fourth of all mortality). Half of these are estimated to be from bacterial infections.
The development of “superbugs” such as vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus, which show wide-spectrum antibiotic resistance, is a serious concern. Despite extensive efforts to control and curtail resistance, there has been a persistent rise in the spread and severity of antibiotic resistance.
It is now believed that it is only a matter of time before some of these bacterial pathogens will become resistant to all clinically used antibiotics. The biochemistry of bacteria and humans differ in several aspects, and these differences can be exploited in order to combat pathogenic bacteria. The design of antibiotics strongly depends on the availability of three-dimensional structures of the bacterial enzymes that are the targets of antibiotics. With the recrudescence of infections caused by antibiotic-resistant pathogenic bacteria, it is necessary to develop new therapies aimed at new biochemical targets, including essential metabolic pathways for bacteria or enzymes responsible for the resistance to antibiotics. Completely novel treatments and treatments which combine classical antibiotic therapy with novel compounds that target antibiotic resistance mechanisms are especially promising.
Structural biology plays a major role by assisting chemists and clinicians in the development of a new generation of antibiotics.
Active CSB initiatives on infectious diseases include:
- Albert Berghuis’ research to understand the mechanisms of antibiotic resistance through structural biology.
- Martin Schmeing’s studies on the natural synthesis of therapeutics by nonribosomal peptide synthetases.
- Gonzalo Cosa’s mechanistic studies of viral genome-replication machinery, inhibitors and associated resistance.
- Bhushan Nagar’s studies on the role of the innate immune system.
- Paul Wiseman’s high-resolution imaging to study malaria.
Synthetic biology is the design and application of biological systems to improve the human condition. It is a field of biological research and technology which combines elements of biology, chemistry, and engineering. One aspect of synthetic biology is the development of bionanomachines. These are nanometer-scale biological devices, such as enzyme complexes, or biomaterials such as spider silk. Through design, we can rework natural bionanomachines to carry out novel chemistries, to act as biosensors, or to show enhanced mechanical properties.
Our understanding of natural bionanomachines is largely based on work in structural biology using X-ray crystallography, NMR spectroscopy, electron microscopy, and molecular modelling. The methods of analysis can be categorized by the size and resolution of the structures they are used to study. Large structures, for example, can be studied at low resolution using super-resolution fluorescence and electron microscopy.
Another branch of synthetic biology includes supramolecular chemistry. Having conceptually disassembled bionanomachines using structural biology, supramolecular chemistry aims to reassemble them in new and innovative ways. This field of science uses non-covalent bonds to construct molecular assemblies with novel properties.
Active CSB initiatives in synthetic biology include:
- Paul Wiseman and Gonzalo Cosa’s innovative single-molecule fluorescence techniques to overcome the diffraction limit in super-resolution fluorescence microscopy.
- Khanh Huy Bui and Martin Schmeing’s use of the latest techniques of electron cryo-microscopy to study lipid, nucleic acid and protein structures
- The application by the Nagar, Schmeing, Trempe, Gehring and Berghuis labs of X-ray crystallography to study a wide variety of bionanomachines ranging from membrane transport systems to enzymes that modify antibiotics.
- Anthony Mittermaier’s uses of NMR spectroscopy to study protein mobility.
- Hanadi Sleiman’s use of DNA as a biological scaffold with incredible properties of self-assembly, facilitating the construction of functional units using non-covalent bonds.
- Masad Damha’s exploration of the design of novel nucleic acids to manipulate cells as potent therapeutics.
- Gary Brouhard’s study of cytoskeletal protein self assembly, which is a key aspect of cell movement, growth and division.