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Bioorg Med Chem Lett. 2002 Nov 4;12(21):3223-7.

Conformational restraint is a critical determinant of unnatural nucleotide recognition by protein kinases.

Author information

1
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-0450, USA. shokat@cmp.ucsf.edu

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.

PMID:
12372539
DOI:
10.1016/s0960-894x(02)00616-9
[Indexed for MEDLINE]

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