title: Effective disruption of phosphoprotein-protein surface interaction using Zn(II) dipicolylamine-based artificial receptors via two-point interaction.
abstract: Protein phosphorylation is ubiquitously involved in living cells, and it is one of the key events controlling protein-protein surface interactions, which are essential in signal transduction cascades. We now report that the small molecular receptors bearing binuclear Zn(II)-Dpa can strongly bind to a bis-phosphorylated peptide in a cross-linking manner under neutral aqueous conditions when the distance between the two Zn(II) centers can appropriately fit in that of the two phosphate groups of the phosphorylated peptide. The binding property was quantitatively determined by ITC (isothermal titration calorimetry), induced CD (circular dichroism), and NMR. On the basis of these findings, we demonstrated that these types of small molecules were able to effectively disrupt the phosphoprotein-protein interaction in a phosphorylated CTD peptide and the Pin1 WW domain, a phosphoprotein binding domain, at a micromolar level. The strategy based on a small molecular disruptor that directly interacts with phosphoprotein is unique and should be promising in developing a designer inhibitor for phosphoprotein-protein interaction.
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Kyoto, 615-8510, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Ojida
authors.forename: Masa-aki
authors.initials: MA
authors.lastname: Inoue
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Mito-oka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsutsumi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sada
authors.forename: Itaru
authors.initials: I
authors.lastname: Hamachi
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D005454:Fluorescence Polarization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009942:Organometallic Compounds / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism*; D010847:Picolines / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D018000:Receptors, Peptide / Q000737:chemistry*; D013499:Surface Properties; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology
chemical_list: D003432:Cross-Linking Reagents; D009942:Organometallic Compounds; D010750:Phosphoproteins; D010847:Picolines; D011506:Proteins; D018000:Receptors, Peptide; C509592:zinc(II) dipicolylamine; D015032:Zinc