Dinuclear copper(II) complexes with valsartan. Synthesis, characterization and cytotoxicity

Two novel dinuclear complexes involving the antihypertensive drug valsartan and copper(II) ion have been prepared in water and DMSO. The complex compositions were determined as: [Cu(vals)(H(2)O)(3)](2)center dot 6H(2)O and [Cu(vals)(H(2)O)(2)DMSO](2)center dot 2H(2)O. They were thoroughly characterized by elemental and thermal analysis, spectrophotometric titrations and UV-visible, diffuse reflectance, FTIR, Raman and EPR spectroscopies. No effect of the ligand on two tested osteoblastic cell lines in culture (one normal MOT3E1 and one tumoral UMR106) was observed in concentrations up to 100 mu M. Higher concentrations of Valsartan are required to induce cytotoxicity in both cell lines. The antiproliferative effect of the tested complex ([Cu(vals) (H(2)O)(3)](2)center dot 6H(2)O) in a dose-response manner, was higher in the UMR106 osteoblastic cell line than that of the MC3T3E1 normal line at concentrations >= 100 mu M. Morphological alterations are in accordance with proliferative observations. (C) 2011 Elsevier Inc. All rights reserved.

Structure of the PilZ-FimXEAL-c-di-GMP complex responsible for the regulation of bacterial type IV pilus biogenesis

Signal transduction pathways mediated by cyclic-bis(3'→5')-dimeric GMP (c-di-GMP) control many important and complex behaviors in bacteria. C-di-GMP is synthesized through the action of GGDEF domains that possess diguanylate cyclase activity and is degraded by EAL or HD-GYP domains with phosphodiesterase activity. There is mounting evidence that some important c-di-GMP-mediated pathways require protein-protein interactions between members of the GGDEF, EAL, HD-GYP and PilZ protein domain families. For example, interactions have been observed between PilZ and the EAL domain from FimX of Xanthomonas citri (Xac). FimX and PilZ are involved in the regulation of type IV pilus biogenesis via interactions of the latter with the hexameric PilB ATPase associated with the bacterial inner membrane. Here, we present the crystal structure of the ternary complex made up of PilZ, the FimX EAL domain (FimXEAL) and c-di-GMP. PilZ interacts principally with the lobe region and the N-terminal linker helix of the FimXEAL. These interactions involve a hydrophobic surface made up of amino acids conserved in a non-canonical family of PilZ domains that lack intrinsic c-di-GMP binding ability and strand complementation that joins β-sheets from both proteins. Interestingly, the c-di-GMP binds to isolated FimXEAL and to the PilZ-FimXEAL complex in a novel conformation encountered in c-di-GMP-protein complexes in which one of the two glycosidic bonds is in a rare syn conformation while the other adopts the more common anti conformation. The structure points to a means by which c-di-GMP and PilZ binding could be coupled to FimX and PilB conformational states