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The 3-D structure of human lactoferrin was first solved in atomic detail in 1987. Since that time, a variety of proven and postulated activities have been added to the original annotation of lactoferrin as an iron-binding protein. Structural studies have also expanded to include iron-bound and iron-free (apo) forms, mutants, and the lactoferrins of different species. In this review, we take the current information on both structure and function and show that the 3-D structure provides a useful framework for understanding some activities and also points to productive research directions that could help elucidate other reported functions. Some functions relate to iron binding where the role of lactoferrin is to scavenge and retain iron across a wide pH range. We specifically focus on functions that depend on the surface structure of the molecule, identifying features that may determine the many other protective properties of this multifunctional protein. Key words: lactoferrin, protein structure, iron binding, protective functions, glycosylation. La structure tridimensionnelle de la lactoferri-ne humaine a ete d'abord resolue a l'echelle atomique en 1987. Depuis lors, une variete d'activites demontrees ou presumees ont ete ajoutees a la premiere indication que la lactoferrine etait une proteine de liaison du fer. Des etudes structurales se sont aussi developpees pour inclure les formes liee et non liee (apo) au fer, les mutants et les lactoferrines de differentes especes. Dans cet article de revue, nous compilons l'information actuelle portant tant sur la structure que la fonction de la lactoferrine, et nous montrons que la structure tridimensionnelle fournit un canevas utile pour comprendre certaines de ses activites et indique certaines directions productives de recherche qui pourraient nous aider a elucider d'autres fonctions connues. Certaines fonctions sont reliees a la liaison du fer ou le role de la lactoferrine est de desactiver et de retenir le fer a travers un large spectre de pH. Nous nous concentrons specialement sur les fonctions qui dependent de la structure de surface de la molecule, identifiant les caracteristiques qui peuvent determiner les nombreuses autres proprietes protectrices de cette proteine multifonctionnelle. Mots-cles : lactoferrine, structure proteique, liaison du fer, fonctions protectrices, glycosylation., Introduction It is just over 50 years since lactoferrin (Lf) was first isolated and characterized from both human and bovine milks (Johanson et al. 1960; Groves 1960; Montreuil et al. [...]

A study employs the X-ray crystallography technique to analyze the high-resolution crystal structure of a plant carboxylesterase, named Actinidia eriantha (AeCXEI), which is found to be closely related to the hormone-sensitive lipase subgroup structurally. The analysis reveals that the compound binds with paraoxon very easily forming a complex without inducing any change in the structure of the enzyme and hence helps in studying the role of carboxylesterases in plants.

Research has been conducted on the proteins of the transferrin family. The role of these proteins in the iron homeostasis in vertebrates has been investigated and discussed.

Crystal structure analysis of the N-lobe half-molecule of human transferrin, which mediates iron transport, reveals a highly conserved iron binding site and hydrogen bonding interaction. Data point out that the binding and release of iron is influenced by the dilysine interaction.

X-ray diffraction studies were conducted to determine the structure of the trigonal crystal form of the beta-lactoglobulin of cows to determine the structural basis of the Tanford transition of this protein. Results of the studies done at different pH levels reveal that conformational changes in the segment spanning amino acid residues 85 to 90 is responsible for the physical and spectroscopic phenomena comprising the Tanford transition of beta-lactoglobulin.

The crystalline structures of the iron-bound, recombinant N-lobe of human serum transferrin has been studied at resolutions 1.6 and 1.8 angstroms. Transferrins are bilobal proteins that bind strongly with ferric iron at two similar binding sites. Both structures have folding patterns that resemble those of previously discovered transferrin and lactoferrin N-lobe structures. Its amino acid sequence has a polypeptide chain that has similar amino- and carboxyl-terminal halves.

Structural and spectral perturbations are seen when oxalate ion is substituted at the binding site for carbonate ion, in lactoferrin protein that belongs to the family of transferrin proteins. However, polypeptide folding and domain closure remain unaffected by the substitution. Oxalate is bound to iron at the C-lobe site of the bilobal transferrin in a symmetric 1,2-bidentate manner, whereas at the N-lobe site, the binding is asymmetric. This happens because oxalate, being a larger anion, displaces the wall forming arginine at the anion binding site.

The binding of copper(II) instead of iron(III) to lactoferrin takes on a different coordination geometry but results in the same protein structure. The substitution, with subsequent crystal structure study, is undertaken to determine the effects of non-Fe metal binding to transferrins. Whereas the two binding sites for iron are the same, copper binds at the N-terminal site via a square pyramidal form and at the C-terminal site with a distorted octahedral. The difference results from the movement of metal ion andanion at each binding site but does not affect the protein structure.

Physicochemical and crystallographic studiesreveal the binding behavior of lactoferrin (Lf) to iron(III) and copper(II). Lfis a glycoprotein that easily binds with iron in biological fluids and thus controls its presence therein. The studies show that binding is done through the carbonate (CO3) anion which locks in bidentate fashion to the metal. Oxalate (C2O4) ions can displace one or both CO3 in a Lf-Cu(II) complex but notin a Lf-Fe(III) complex. In the hybrid (CO3-C2O4) complex, which results when alittle EDTA is present, the CO3 binds specifically at the C-lobe, displacing nearby side chains. A generalized model for anion binding is developed from these results.

The crystal structure characterization of lipoprotein MtsA, a component of the MtsABC transporter of Streptococcus pyogenes to understand the bacterial metal binding receptor (MBR) fold of MtsA with the [Fe.sup.2+] ion bound to the side chains of His68, His140, Glu206, and Asp281, at a totally enclosed site between the two domains of the protein. The mutational analysis of the binding site provide insight into the critical role of His140 towards fully functional binding site and other secondary binding sites that might explain the binding behavior of MtsA for metal ions other than [Fe.sup.2+].

The structural characterization of six new depsipeptides belonging to two different structural classes, celebesides A-C and theopapuamides B-D, isolated from the marine sponge Siliquariaspongia mirabilis is described. Theopapuamide A-C has exhibited strong antifungal activity toward amphotericin B-resistant Candida albicans and its parent strain, whereas celebesides has displayed anti-HIV activity due to presence of phosphoserine.