4B8Y

Ferrichrome-bound FhuD2

Summary for 4B8Y

• Entry DOI: 10.2210/pdb4b8y/pdb
• Descriptor: FHUD2, VIRULENCE FACTOR, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: transport protein-siderophore complex, transport protein, vaccine, siderophore, class iii solute binding, inhibitor protein (sbp), transport protein/siderophore
• Biological source: STAPHYLOCOCCUS AUREUS SUBSP. AUREUS NCTC 8325; More
• Total number of polymer chains: 2
• Total formula weight: 32793.67

Authors

Malito, E.,Bottomley, M.J.,Spraggon, G. (deposition date: 2012-08-31, release date: 2012-11-21, Last modification date: 2023-12-20)

Primary citation

Mariotti, P.,Malito, E.,Biancucci, M.,Lo Surdo, P.,Mishra, R.P.,Nardi-Dei, V.,Savino, S.,Nissum, M.,Spraggon, G.,Grandi, G.,Bagnoli, F.,Bottomley, M.J.
Structural and Functional Characterization of the Staphylococcus Aureus Virulence Factor and Vaccine Candidate Fhud2.
Biochem.J., 449:683-, 2013

PubMed Abstract: Staphylococcus aureus is a human pathogen causing globally significant morbidity and mortality. The development of antibiotic resistance in S. aureus highlights the need for a preventive vaccine. In the present paper we explore the structure and function of FhuD2 (ferric-hydroxamate uptake D2), a staphylococcal surface lipoprotein mediating iron uptake during invasive infection, recently described as a promising vaccine candidate. Differential scanning fluorimetry and calorimetry studies revealed that FhuD2 is stabilized by hydroxamate siderophores. The FhuD2-ferrichrome interaction was of nanomolar affinity in surface plasmon resonance experiments and fully iron(III)-dependent. We determined the X-ray crystallographic structure of ligand-bound FhuD2 at 1.9 Å (1 Å=0.1 nm) resolution, revealing the bilobate fold of class III SBPs (solute-binding proteins). The ligand, ferrichrome, occupies a cleft between the FhuD2 N- and C-terminal lobes. Many FhuD2-siderophore interactions enable the specific recognition of ferrichrome. Biochemical data suggest that FhuD2 does not undergo significant conformational changes upon siderophore binding, supporting the hypothesis that the ligand-bound complex is essential for receptor engagement and uptake. Finally, immunizations with FhuD2 alone or FhuD2 formulated with hydroxamate siderophores were equally protective in a murine staphylococcal infection model, confirming the suitability and efficacy of apo-FhuD2 as a protective antigen, and suggesting that other class III SBPs might also be exploited as vaccine candidates.

PubMed: 23113737
DOI: 10.1042/BJ20121426

Experimental method

X-RAY DIFFRACTION (1.9 Å)