STRUCTURE OF HAEMOPHILUS-INFLUENZAE FE-BINDING PROTEIN REVEALS CONVERGENT EVOLUTION WITHIN A SUPERFAMILY(3)

The first crystal structure of the iron-transporter ferric ion-binding protein from Haemophilus influenzae (hFBP), at 1.6 Angstrom resolutio n, reveals the structural basis for iron uptake and transport required by several important bacterial pathogens. Paradoxically, although hFB P belongs to a protein superfamily which includes human transferrin, i ron binding in hFBP and transferrin appears to have developed independ ently by convergent evolution. Structural comparison of hFBP with othe r prokaryotic periplasmic transport proteins and the eukaryotic transf errins suggests that these proteins are related by divergent evolution from an anion-binding common ancestor, not from an iron-binding ances tor. The iron binding site of hFBP incorporates a water and an exogeno us phosphate ion as iron ligands and exhibits nearly ideal octahedral metal coordination. FBP is highly conserved, required for virulence, a nd is a nodal point for free iron uptake in several Gram-negative path ogenic bacteria, thus providing a potential target for broad-spectrum antibacterial drug design against human pathogens such as H. influenza e, Neisseria gonorrhoeae, and Neisseria meningitidis.