title: ITAM-derived phosphopeptide-containing dendrimers as multivalent ligands for Syk tandem SH2 domain.
abstract: Spleen tyrosine kinase (Syk) is activated when its tandem SH2 domain (tSH2) binds to a diphosphorylated ITAM motif of e.g. the FcepsilonRI receptor. In this divalent interaction each SH2 domain binds to a phosphotyrosine-containing tetrapeptide motif in ITAM. One of those tetrapeptide sequences was synthesized and conjugated to dendrimers via 'click' chemistry to create a series of functional phosphopeptide-containing dendrimers ranging from a monovalent to an octavalent dendrimer. The affinity of the functionalized dendrimers for Syk tSH2 has been assayed in SPR competition experiments. Both the tetra- and octavalent dendrimer had an affinity in the high nanomolar range, which is approximately 100-fold enhanced compared to the monovalent tetrapeptide, indicating a multivalency effect.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Medicinal Chemistry & Chemical Biology, PO Box 80082, Utrecht, 3508 TB, Netherlands.
authors.forename: Joeri
authors.initials: J
authors.lastname: Kuil
authors.forename: Hilbert M
authors.initials: HM
authors.lastname: Branderhorst
authors.forename: Roland J
authors.initials: RJ
authors.lastname: Pieters
authors.forename: Nico J
authors.initials: NJ
authors.lastname: de Mol
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
mesh_terms: D000480:Alkynes / Q000737:chemistry; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000737:chemistry*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D000072377:Syk Kinase; D014443:Tyrosine; D018909:src Homology Domains
chemical_list: D000480:Alkynes; D050091:Dendrimers; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D010748:Phosphopeptides; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse