The three-dimensional structure of human lactoferrin (Lf) was determined by X-ray crystallography in 1987. Three-dimensional structures are now available for other Lfs (bovine, horse and buffalo), for various functional and conformational states, and for recombinant Lfs and site-specific mutants. The picture that emerges is of a protein with highly conserved folding and essentially invariant metal and anion binding sites. Within this conserved framework various kinds of flexibility and variation occur; large domain movements accompany iron binding and release, and local sequence differences lead to changes on the protein surface, or in the domain or lobe interfaces. The ability of Lf to retain iron to much lower pH than its close relative transferrin appears to be due to a pair of basic amino acids close to the N-lobe binding site, and to interlobe communication. Other activities of Lf appear to be mostly related to a highly positively charged region of the surface of the N-lobe (the N-terminus and neighbouring first helix). This region varies somewhat between different species, suggesting that comparative studies with different Lfs would establish which are universal properties and which are species-specific.
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