title: [Reversible metalation of a bis-disulfide analogue of the Cys*-X-Cys* hepcidin binding site: structural characterisation of the related copper complex].
abstract: Hepcidin, a 25-amino-acid peptide secreted by the liver, distributed in the plasma and excreted in urine, is a key central regulator of body iron homeostasis. This hormone decreases export of cellular iron by binding to ferroportin, an iron exporter present at the basolateral surface of enterocytes and macrophages (the sites of dietary iron absorption and iron recycling, respectively), inducing its internalization and degradation. Hepcidin contains eight cysteine residues that form four disulfide bridges, which stabilize a hairpin-shaped structure with two beta sheets. We noticed in the sequence of hepcidin a Cys*-X-Cys* motif which can act as a metal binding site able to trap iron and/or copper. We have tested this hypothesis using a pseudopeptidic synthetic bis-disulfide analogue and we have shown that direct metalation of such ligand leads to the formation of a copper(III) complex with the typical N(2)S(2) donor set. This compound crystallizes in the orthorhombic system, space group Imma. The Cu(III) configuration is square planar, built up from two carboximado-N and two thiolato-S donors. This complex is converted back to the bis-disulfide, with release of the copper salt, upon oxidation with iodine.
authors.affiliation: UMR 8015/CNRS, laboratoire de cristallographie et RMN biologiques, université Paris Descartes, 4 avenue de l'Observatoire, Paris cedex 06, France.
authors.forename: N
authors.initials: N
authors.lastname: Desbenoit
authors.forename: E
authors.initials: E
authors.lastname: Galardon
authors.forename: P
authors.initials: P
authors.lastname: Deschamps
authors.forename: P
authors.initials: P
authors.lastname: Roussel
authors.forename: S
authors.initials: S
authors.lastname: Vaulont
authors.forename: I
authors.initials: I
authors.lastname: Artaud
authors.forename: A
authors.initials: A
authors.lastname: Tomas
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D001665:Binding Sites; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry*; D064451:Hepcidins; D007501:Iron / Q000378:metabolism; D008024:Ligands; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D013440:Sulfides / Q000737:chemistry
chemical_list: D023181:Antimicrobial Cationic Peptides; D004220:Disulfides; D064451:Hepcidins; D008024:Ligands; D013440:Sulfides; D003300:Copper; D007501:Iron; D003545:Cysteine; C033479:sodium sulfide