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Title: Structural basis of antibacterial peptide transport across membranes
Author: Mathavan, Indran
ISNI:       0000 0004 5918 4481
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Microcins are gene encoded antibacterial peptides secreted by enterobacteria in the gastrointestinal tract and play an important role in the control of bacterial populations. They present an attractive prospect in our effort to minimize the problem of bacterial drug resistance. Microcin J25 (MccJ25) is a 2 kDa plasmid encoded, ribosomally synthesized antimicrobial peptide comprised of 21 amino acid residues. MccJ25 undergoes post-translational modification and has a unique lasso structure. McjD, an ABC exporter, confers immunity to the producing strains by exporting the mature MccJ25 out of the cell. Studies have been designed to look into the transport mechanism of this peptide, which uses the siderophore receptor FhuA and ABC transporter McjD. MccJ25 uses the Trojan horse strategy by hijacking the iron import machineries as a mode of transport into the cell and acts as a transcription inhibitor by binding to RNA polymerase. Iron is an important nutrient for bacteria cell survival. To date, there is limited structural evidence on the import and extrusion mechanism of this antimicrobial peptide in Gram-negative bacteria. We have obtained a high-resolution structure of MccJ25 with its outer membrane receptor FhuA at 2.3 Å. FhuA is monomeric 22-strand antiparallel β-barrel protein with the N-terminal domain folded inside to form a plug domain. MccJ25 binds to FhuA with hydrogen bonds and hydrophobic interactions with the extracellular loops of FhuA and its plug domain. We have also identified key residues that might play a role in MccJ25 translocation. Overall the structure provides information on how MccJ25 hijacks the iron uptake pathway to get into bacteria. Ligand binding studies and biochemical analysis demonstrate the functionality of McjD and its interaction with its natural ligand, MccJ25. The high substrate specificity and known cavity make McjD an excellent model for interaction studies.
Supervisor: Beis, Konstantinos Sponsor: MOSTI ; Malaysia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral