title: Macrocyclization of the ATCUN motif controls metal binding and catalysis.
abstract: We report the design, synthesis, and characterization of macrocyclic analogues of the amino-terminal copper and nickel binding (ATCUN) motif. These macrocycles have altered pH transitions for metal binding, and unlike linear ATCUN motifs, the optimal cyclic peptide 1 binds Cu(II) selectively over Ni(II) at physiological pH. UV-vis and EPR spectroscopy showed that cyclic peptide 1 can coordinate Cu(II) or Ni(II) in a square planar geometry. Metal binding titration and ESI-MS data revealed a 1:1 binding stoichiometry. Macrocyclization allows for coordination of Cu(II) or Ni(II) as in linear ATCUN motifs, but with enhanced DNA cleavage by the Cu(II)-1 complex relative to linear analogues. The Cu(II)-1 complex was also capable of producing diffusible hydroxyl radicals, which is unique among ATCUN motifs and most other common copper(II) chelators.
authors: Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford, Massachusetts 02155, United States.
authors: Kosh P
authors: KP
authors: Neupane
authors: Amanda R
authors: AR
authors: Aldous
authors: Joshua A
authors: JA
authors: Kritzer
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D003500:Cyclization; D006863:Hydrogen-Ion Concentration; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009532:Nickel / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification
chemical_list: D047028:Macrocyclic Compounds; D009942:Organometallic Compounds; D010456:Peptides, Cyclic; D003300:Copper; D009532:Nickel