FhuD: Difference between revisions

<applet load='1esz' size='400' frame='true' align='right' caption='Strucutre of the Periplasmic Ferric Siderophore Binding Protein FhuD complexed with Albomycin as determined by Clarke et al.' />

Siderophore-binding proteins can be found in both Gram-positive and Gram-negative bacteria in divisions: hydroxamates, catecholates, and carboxylates.<ref name="lu">PMID: 11805094</ref>  In Escherichia coli. (E. coli) the ATP-binding cassette- type (ABC-type) protein FhuD (part of the ��helical backbone�� metal receptor superfamily) is a common periplasmic protein which facilitates the transport of a variety of hydoxamate siderophores to the inner membrane-associated proteins FhuB and FhuC.<ref name="lu"/> The structure of FhuD is atypical for periplasmic ligand binding protein due to its bilobal mixture of two α/β domains connected by long α-helix.<ref name="lu"/>,<ref name="la">PMID: 10742172</ref>

FhuD structure is atypical for periplasmic ligand binding proteins. It is 266 residues in length containing a secondary structure composed of 41% helical (13 helices; 110 residues) and 17% beta sheet (13 strands; 47 residues).<ref name="lu"/> It is a bilobal kidney bean shape with approximate dimensions 60 Å ´ 30 Å ´ 40 Å. containing two domains which are connected by a 23-residue kinked α-helix.<ref name="lu"/>,<ref name="la"/> The <scene name='Sandbox_193/N-terminal_domain/1'>N-terminal domain (green)</scene> (residues 27–141) twisted fived-stranded parallel β-sheet with 3-2-1-4-5 linking topology whereas the C-terminal domain (residues 166–288) has a mixed five stranded β-sheet 3-2-1-4-5 linking topology; both are enclosed by α-helices. Between the two domains lies the shallow siderophore <scene name='Sandbox_193/Binding_pocket/1'>binding site (pink)</scene> approximate 10 Å deep which forms depression or “pocket.”<ref name="lu"/>,<ref name="la"/> This pocket is lined with hydrophobic residues which side chain residues are able to create stabilizing hydrogen bonds with the accepted siderophore.<ref name="lu"/> This is large enough to accommodate the hydrophobic orinthyl linkers of the siderophore.<ref name="lu"/> Through rearrangements of the residues of the binding pocket and interactions with the iron-hydroxamate centers of the siderophore, recognition can occur with structurally diverse siderophores.<ref name="lu"/> The binding diversity is further increased since the siderophore backbones do not interact with the proteins.<ref name="lu"/> The structure of the binding pocket of FhuD allows molecules like coprogen bound to a siderophore to form several important hydrogen bonds to create a stable interaction for transportation. A hydrogen bond is formed between the hydroxamate oxygen opposite to the diketopiperazine ring and the terminal amine of Arg-84.<ref name="lu"/> The other hydroxamate oxygen forms a hydrogen bond with the hydroxyl group of Tyr-106.<ref name="lu"/> These hydrogen bonds are found in the iron coordinating components of the siderophore. This is similiar to Alboymcin which forms three protein-ligand hydrogen bonds between Arg-84 and Tyr-106.<ref name="lu"/> Two between the terminal amino groups of Arg-84 and the hydroxamate siderophore and another between the remaining hydroxamate to the hydroxyl group of Tyr-106.<ref name="lu"/> Slight movement of  interactions between these residues are significant to FhuD`s ability to produce binding specificity and correct fit.<ref name="lu"/>  

Unlike other periplasmic ligand binding protein (PLBP), FhuD does not have the characteristic fold of a bilobate domain connected by flexible β-strands at the base of the ligand binding pocket.<ref name="lu"/> This results in FhuD adopting a novel PLBP structure.<ref name="lu"/> As designated by its structure, FhuD binds hydroxamate siderophores into a primarily hydrophobic pocket allowing the assumption that both binding and release do not cause large scale opening/closing.<ref name="la"/> However in the binding pocket, several major ligand binding side chains have been noted in various positions depending on the ligand bound.<ref name="lu"/>,<ref name="la"/> Due to the ability of siderophore binding uptake systems to allow such a diverse array of siderophore bound molecules, new bacterial growth inhibiting agents may be developed.<ref name="lu"/> These agents will be delivered into the bacteria as silent “Trojan Horses” by the bacteria’s own uptake system.<ref name="lu"/>