Locating protein-bound metal ions to accelerate drug design and discovery
LEAD SUPERVISOR: Prof Peter McHugh, Department of Oncology
Co-supervisor: Prof Christopher J. Schofield, Department of Chemistry
Commercial partner: Johnson Matthey, Reading
Many important drug target proteins bind metal ions, where the biological chemistry of the proteins depends on coordinated metal ions. One-third of all known proteins bind metal ions and the characterisation of metal ion-binding sites is important for understanding protein function and development of new drugs. Metal ions play crucial roles in protein structure and function, with classic examples including the role of iron ions in O2 transport by haemoglobin, the role of zinc fingers in gene expression, and the regulation of calcium ions in signalling . However, identifying and locating metal ions bound in proteins remains a major bottleneck in the development of drugs targeting these proteins. To accelerate drug discovery, new methods for identifying and quantifying metal ion occupancy are required.
Our project will focus on the metallo-β-lactamase (MBL) enzyme superfamily. Bacterial MBLs are metal ion-dependent hydrolases that enable resistance to almost all β-lactam antibiotics, e.g. penicillins. Human nuclease enzymes with an MBL fold enable resistance to common chemotherapy drugs, such as cisplatin. As no good methods currently exists to visually confirm the metal binding site, we propose the development of reliable methods to identify and locate metal ions from relatively small amounts of starting material – information that will be crucial to development of new cancer drugs targeting MBL fold nucleases.
The scientific focus will be:
• Defining physiologically relevant biochemical functions of the (several) medically-important uncharacterised human MBL fold enzymes.
• Understanding mechanisms of the MBL enzymes catalysing reactions using biochemical and structural methods including crystallography and cryoEM and cryoSTEM.
• Identifying the metals used by MBL enzymes in cells and understanding/probing the metal selectivity of MBL enzymes.
The student will also work with team members developing new MBL inhibitors to tackle drug resistance, harnessing the improved knowledge of metal ion occupancy to iteratively improve candidate inhibitors.
Apply using course: DPhil in Oncology