title: Predicting the disruption by UO2(2+) of a protein-ligand interaction.
abstract: The uranyl cation (UO(2) (2+)) can be suspected to interfere with the binding of essential metal cations to proteins, underlying some mechanisms of toxicity. A dedicated computational screen was used to identify UO(2) (2+) binding sites within a set of nonredundant protein structures. The list of potential targets was compared to data from a small molecules interaction database to pinpoint specific examples where UO(2) (2+) should be able to bind in the vicinity of an essential cation, and would be likely to affect the function of the corresponding protein. The C-reactive protein appeared as an interesting hit since its structure involves critical calcium ions in the binding of phosphorylcholine. Biochemical experiments confirmed the predicted binding site for UO(2) (2+) and it was demonstrated by surface plasmon resonance assays that UO(2) (2+) binding to CRP prevents the calcium-mediated binding of phosphorylcholine. Strikingly, the apparent affinity of UO(2) (2+) for native CRP was almost 100-fold higher than that of Ca(2+). This result exemplifies in the case of CRP the capability of our computational tool to predict effective binding sites for UO(2) (2+) in proteins and is a first evidence of calcium substitution by the uranyl cation in a native protein.
authors.affiliation: CEA Life Sciences Division, DSV, IBEB, SBTN, Bagnols-sur-Cèze, F-30207, France. olivier.pible@cea.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Pible
authors.forename: Claude
authors.initials: C
authors.lastname: Vidaud
authors.forename: Sophie
authors.initials: S
authors.lastname: Plantevin
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Pellequer
authors.forename: Eric
authors.initials: E
authors.lastname: Quéméneur
mesh_terms: D000465:Algorithms; D002097:C-Reactive Protein / Q000737:chemistry / Q000378:metabolism; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002412:Cations / Q000737:chemistry; D003198:Computer Simulation; D057225:Data Mining; D030562:Databases, Protein; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D016011:Normal Distribution; D010767:Phosphorylcholine / Q000737:chemistry / Q000378:metabolism; D011402:Pronase / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D015203:Reproducibility of Results; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D013305:Streptomyces griseus / Q000201:enzymology; D020349:Surface Plasmon Resonance; D013816:Thermodynamics; D014501:Uranium / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002412:Cations; D008024:Ligands; D011506:Proteins; D012709:Serum Albumin; D010767:Phosphorylcholine; D014501:Uranium; D002097:C-Reactive Protein; D011402:Pronase; D002118:Calcium