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Title: Metal clusters in a bacterial iron-trafficking protein
Author: Zhu, Haizhong
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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Bacterial resistance to standard antibiotic therapies is a critical health protein worldwide. Antimicrobial-resistant infections that are essentially untreatable have begun to occur as epidemics around the globe. In this thesis, I have used the techniques of coordination chemistry, molecular biology, and protein x-ray crystallography to study metal binding of ferric ion binding protein (Fbp). Fbp is a highly-conserved 34 kDa periplasmic iron transporter, a candidate as target for novel metalloantibiotic design. I have discovered that the characteristic dityrosyl motif of Fbp from the human pathogen Neisseria gonorrhoeae can assemble/bind metal clusters in the open metal-binding cleft of the protein, although closure of the hinged metal-binding cleft and the presence of the synergistic phosphate anion are usually considered obligatory for strong metal binding by Fbp. I have also observed that the phosphate ion in the crystal structure of apo-Fbp can be displaced by mononuclear [Hf(NTA)2]2-, mononuclear [Fe(NTA)2]3- and binuclear [Fe2 (cit)2(H2O)2]2-, yielding a range of oxo Hf(IV) clusters containing from 3 to 5 metal ions, and oxo Fe(III) clusters containing 3 metal ions. Structural comparisons among the crystal structures of apo-Fbp (1.9 A resolution) and the Hf-bound form of Fbp (1.7 A resolution) and Fe-NTA-Fbp (1.8 A resolution) and Fe3-FBP (1.8 A resolution) show no hinge closure upon metal binding, suggesting a novel metal acquisition mechanism. The binding of vanadate to apo-FBP has been studied by 51V NMR, and the data suggest that vanadate can bind similarity to phosphate and also as a vanadium cluster. Crystals of V-Fbp were obtained which diffract to 2.0 A. The work reveals the possibility that bacterial metal uptake is mediated by novel Fbp intermediates including cluster adducts.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available