Host: Dario Alessi

Venue: MSI Small Lecture Theatre, SLS

This seminar is fully funded by external sources

T-cell activity contributes to the pathophysiology of organ transplant rejection, multiple autoimmune diseases and the side effects of cancer immunotherapies. Lymphocyte specific kinase (Lck) is an essential component of signalling in T-cells and acts immediately downstream of the T-cell receptor (TCR). Loss-of-function mutations of Lck in humans result in severe defects in the immune response and pointed to this enzyme as a drug target in T-cell driven autoimmune disease. Auto-transphosphorylation of tyrosine 394 (Y394) on the activation loop of Lck is required for activity. This phosphorylation is sensitive to ATP site directed inhibitors, including the multi-target kinase clinical drug dasatinib. While studying the molecular pharmacology of dasatinib on Lck and the TCR signalling pathway, we saw an unexpected increase in Y394 phosphorylated Lck at ultra-low (1 nM) dasatinib concentrations, while TCR signalling was reduced by 50%. In-depth exploration of this paradoxical effect revealed that dasatinib likely selects or “locks in” a specific phosphorylated Y394 state, making it less sensitive to phosphatase activity. To understand more about the effect of dasatinib on the structure of the Lck kinase domain, a new KNIME programmable workflow was developed, combining homology modelling by MODELLER and molecular docking with GOLD. This identified a protein conformation capable of reproducibly predicting dasatinib binding in a native-like pose and separating the drug from related decoy molecules. The best model was then used in 4 μs molecular dynamics simulations of the kinase domain. Clustering of the Lck conformations in the simulation identified a novel structure, present for most of the dasatinibbound Lck simulation but not observed in either the apo enzyme or with an ATP-directed inhibitor that did not cause the paradoxical increase. The phospho-Y394 bearing activation loop in the apo kinase domain showed substantial movement and solvent exposure of this regulatory residue. In contrast, in the dasatinib-containing simulation the new conformation buried the phosphorylated Y394 residue and likely protects it from dephosphorylation. This novel dasatinib mechanism provides new routes for discovery of inhibitors targeting Lck regulation and ultimately immune dysfunction.

Host: Prof Nicola Stanley-Wall  

  Online Seminar  

All staff/students are encouraged to attend online in support of the school seminar series 

  Bacterial predators are ubiquitous in soil ecosystems, suggesting they play fundamental roles in maintaining these environments. However, their direct functions remain elusive due to limited knowledge of their interactions within real ecological niches. This knowledge gap arises from a lack of methods to bridge laboratory research, often conducted in reductionist settings, with field studies in natural soils. In this presentation, I will discuss our research on Myxococcus xanthus, a soil bacterium that preys collectively by swarming through prey colonies, killing and feeding via direct contact. I will highlight recent findings on the mechanisms by which these bacteria kill and consume their prey and explore how these processes operate within their natural ecological context. 

Meeting ID: 344 368 389 540

Passcode: hpMZeJ