X-ray Crystallographic Structures of the Escherichia coli Periplasmic Protein FhuD Bound to Hydroxamate-type Siderophores and the Antibiotic Albomycin

Abstract

consists of an antibiotic group attached to a hydroxamate siderophore, electron density for the antibiotic portion was not observed. Therefore, this study provides a basis for the rational design of novel bacteriostatic agents, in the form of siderophore-antibiotic conjugates that can act as "Trojan horses," using the hydroxamatetype siderophore uptake system to actively deliver antibiotics directly into targeted pathogens.

Characterization of a Bacillus subtilis transporter for petrobactin, an anthrax stealth siderophore

“…S3) assume approximately the same positions as the CeuE conserved residues Arg-118, Arg-205, Arg-249, and Tyr-288, which directly contact ferric mecam (30). In other similar structures, particularly FhuD (1efd) and FeuA (2phz), only Arg-104 and Tyr-275 are well conserved (31,32). The chargepotential surface drawing of YclQ, with a positively charged pocket to accommodate a negatively charged FePB, is also similar to those of CeuE and FeuA (Fig.…”

“…The structures of E. coli PBP FhuD complexed with a number of hydroxamate siderophores, such as gallichrome (1efd), albomycin ␦2 (1k7s), coprogen (1esz), and DFO (1k2v), which are also structurally similar to YclQ with Z values near 7.0 and rmsd of 2.7 Å. However, the sequence identity is only about 17% (31,32). There are a number of other PBP structures, including bacterial hemebinding protein (2rg7, 2r7a, and 2r79), IsdE complexed with heme (2q8q), periplasmic iron(III)-binding protein (2etv), and BtuF complexed with vitamin B12 (1n4a and 1n2z) with similarities ranging (by Z values) from 4 to 6 with rmsd's of 2.6 Å or higher, depending on the size and the ligand; however, their sequence identities to YclQ are all below 20%.…”

Interactions between TonB from Escherichia coli and the Periplasmic Protein FhuD

“…The crystal structure of FhuD in complex with gallichrome, a ferrichrome analogue, has been reported (12), as well as structures of FhuD in complex with albomycin, coprogen, and Desferal (13). The fold of this 32-kDa protein is bilobal; globular N-and C-terminal domains are connected by a long ␣-helix that confers rigidity to the protein.…”

The Role of FhuD2 in Iron(III)-Hydroxamate Transport in Staphylococcus aureus

“…Indeed, crystal structures of apo and holo forms of BtuF indicate a relatively minor conformational change upon ligand binding (5). High resolution structures of E. coli FhuD bound to different hydroxamate siderophores have been determined (3,4). These structures identify a shallow binding pocket that exists between the two protein domains; siderophores are recognized by the side chains of a few key residues lining the binding pocket.…”

“…Indeed, the closure of the two domains around the ligand has been likened to the active motion of a Venus flytrap. Recent x-ray crystallographic studies have defined a new class of binding proteins that include Escherichia coli FhuD (3,4), which binds iron(III)-hydroxamates; E. coli BtuF (5, 6), which binds vitamin B 12 ; and Treponema pallidum TroA (7), a zinc-binding protein. These proteins possess an architecture that differs from the sugar-and amino acid-binding proteins (represented by MBP) in that they have adopted a single, more inflexible backbone ␣-helix that connects two globular domains.…”