MEMBRANE PROTEIN CRYSTALLOGRAPHY
Membrane proteins represent around 30% of the proteomes of most organisms and more than 40% of drug targets and yet few structures of these molecules have been solved by x-ray crystallography. Drug resistance of bacterial pathogens is a rising crisis. Bacterial membrane proteins are essential for resistance since they are involved in the export of the drugs from the cell. My group is interested in the structural and functional characterisation of multidrug membrane transporters by X-ray crystallography.
We are also interested to exploit novel antibacterials as treatments for bacterial infections.
Bacteria under nutrient starvation can produce antibacterial peptides that hijack outer and inner membrane proteins for internalisation and cell death. These peptides are also toxic to the producing bacteria which utilise ABC-transporters to provide them with immunity. We have solved the structure and fully characterised the ABC-transporter McjD. The protein is in an outward-occluded state and provides key mechanistic information on this family of transporters.
We also solved the structure of the outer membrane FhuA in complex with the antibacterial peptide MccJ25. The structure explains how antibacterial peptides can hijack the outer membrane and be internalised.
et al., 2018, Structural Basis for Natural Product Selection and Export by Bacterial ABC Transporters, Acs Chemical Biology, Vol:13, ISSN:1554-8929, Pages:1598-1609
et al., 2018, Substrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site, Nature Communications, Vol:9, ISSN:2041-1723
et al., 2017, Structural basis for antibacterial peptide self-immunity by the bacterial ABC transporter McjD, Embo Journal, Vol:36, ISSN:0261-4189, Pages:3062-3079
et al., 2016, Structural and Functional Basis for Lipid Synergy on the Activity of the Antibacterial Peptide ABC Transporter McjD, Journal of Biological Chemistry, Vol:291, ISSN:0021-9258, Pages:21656-21668
et al., 2015, Conformational Changes of the Antibacterial Peptide ATP Binding Cassette Transporter McjD Revealed by Molecular Dynamics Simulations, Biochemistry, Vol:54, ISSN:0006-2960, Pages:5989-5998