title: Conformational restraint is a critical determinant of unnatural nucleotide recognition by protein kinases.
abstract: This report describes the synthesis of N(4)-(benzyl) AICAR triphosphate, a conformationally restrained analogue of N(4)-(benzyl) ribavirin triphosphate. Both of these nucleotides were evaluated as phosphodonors for wild-type p38MAP kinase and T106G p38MAP kinase, a designed mutant with expanded nucleotide specificity. The conformationally restrained nucleotide, N(4)-(benzyl) AICAR triphosphate, is orthogonal to (not accepted as a substrate by) wild-type p38MAP kinase, in contrast to N(4)-(benzyl) ribavirin triphosphate. Furthermore, N(4)-(benzyl) AICAR triphosphate, is accepted as a substrate by T106G p38MAP kinase, in contrast to N(4)-(benzyl) ribavirin triphosphate. We hypothesize that the presence of an internal hydrogen bond in N(4)-(benzyl) AICAR and its absence in N(4)-(benzyl) ribavirin triphosphate is the main determinant for their differing structure-activity relationships.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-0450, USA. shokat@cmp.ucsf.edu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Ulrich
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Sallee
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D009154:Mutation; D009711:Nucleotides / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012254:Ribavirin / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014443:Tyrosine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D009711:Nucleotides; D014443:Tyrosine; D012254:Ribavirin; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases