Biomolecular self-assembly is at the heart of all biological processes. It can be defined as the process by which molecules are assembled into the complex architecture of living cells and tissues. Eminent experts in this area from across the Commonwealth will discuss their work, which includes the design of anti-influenza drugs, the study of virus evolution, cellular organisation and signalling, and cell death.
Crystal structures of proteins are integral to contemporary drug discovery. Images in atomic detail of proteins, such as those essential to the life cycle of a virus or to the survival of cancer cells, underpin the work of medicinal chemists in fashioning drugs that bind their target with high affinity and high selectivity.
In the 1980s, the crystal structure of the influenza virus neuraminidase inspired the discovery of a new class of antiviral medicines - the Neuraminidase Inhibitors - Relenza and Tamiflu being the first approved. These drugs target an invariant site on the virus and, unlike current vaccines, are effective against most wild strains of influenza.
Finding drugs that inhibit enzymes, especially extracellular enzymes like the neuraminidase, is less challenging than blocking intracellular protein-protein interactions. An attractive approach to killing certain types of tumour cell is to directly activate the cell’s suicide machinery, and that requires a cell-premeable drug molecule that can perform the function of a helical protein. A number of molecules of this type have now been reported, with one of them advancing in 2014 to phase 3 clinical trials for chronic lymphocytic leukaemia.
The Inhibitors of Apoptosis (IAPs) are multifunctional proteins with roles in cell death, signalling, innate immunity and oncogenesis. Two IAP family members (cIAP1 and cIAP2) control, through their E3 ubiquitin ligase functions, the assembly and activity of key signalling complexes such as the inflammasome, ripoptosome and the necrosome. Small molecule compounds that target the IAPs, known as Smac mimetics, are currently under intense clinical development for the treatment of cancer. Smac mimetics preferentially sensitize tumor cells, compared to normal cells, to the death-inducing properties of cytokines, in particular TNFalpha and TRAIL.
To date, no effective approach at providing these cytokine death triggers to a cancer patient, in combination with a Smac mimetic, has been attempted. We have shown in preclinical mouse models of cancer that the administration of oncolytic viruses, or synthetic Toll-receptor agonists, can induce a systemic but safe cytokine storm, which can then potently synergize with a Smac mimetic to effectively eradicate tumors. We predict that this simple combinatorial cancer immunotherapy approach, which can be easily tested in the clinic, will ultimately become a standard of care for the treatment of cancer.
The plasma membrane of the cell, is a flimsy four, nanometer thick material where proteins are ‘dissolved’ in a fluid-like lipid bilayer, encapsulating the cell within. The membrane has a complex protein and lipid composition, maintained by many active energy-consuming processes such as synthesis, transport and exo-, endocytosis. Cells sense their extracellular milieu via a wide repertoire of membrane receptors embedded in this lipid layer, continuously communicating vital information via these information-transducers. When reconstituted outside the cell, the same lipid and protein constituents of the membrane form a thermodynamic mixture at physiological temperatures, whereas in a living cell, they exhibit remarkable lateral heterogeneities in their organization. These lateral heterogeneities facilitate the establishment of very specific local environments in the vicinity of these information-transducing receptors, necessary for their function. In turn, this allows a cell to respond to and interpret its physical and chemical environment. This raises a very fundamental question- how can the living cell surface, envisaged as a fluid bilayer, regulate its local membrane composition and shape so as to effect function? In this talk I will discuss how the cell constructs biomolecular assemblies by the active engagement of energy consuming machinery.
Lead image: 3D illustration of the influenza virus (flu)Download calendar
Sir John Skehel FRS Biological Secretary and Vice-President, Royal Society (UK)
Professor Peter Colman FRS Division Head, Structural Biology, Walter and Eliza Hall Institute of Medical Research (Australia)
Professor Robert Korneluk Principal Investigator, CHEO Research Institute (Canada)
Professor Satyajit Mayor Director, National Centre for Biological Sciences (India)
Professor Wolf-Dieter Schubert Department of Biochemistry, University of Pretoria (South Africa)
Professor David Stuart FRS MRC Professor of Structural Biology, University of Oxford