Molecular forceps from combinatorial libraries prevent the farnesylation of Ras by binding to its carboxyl terminus

Dong, D. L., Liu, R., Sherlock, R., Wigler, M. H., Nestler, H. P. (March 1999) Molecular forceps from combinatorial libraries prevent the farnesylation of Ras by binding to its carboxyl terminus. Chem Biol, 6 (3). pp. 133-41. ISSN 1074-5521 (Print)

URL: https://www.ncbi.nlm.nih.gov/pubmed/10074468
DOI: 10.1016/S1074-5521(99)89005-X

Abstract

INTRODUCTION: Ras is one of the major oncogenes. In order to function properly it has to undergo post-translational processing at its carboxyl terminus. It has been shown that inhibitors of farnesyl transferase, the first enzyme in the processing chain, can suppress the transforming activity of oncogenic Ras. RESULTS: We have identified molecular forceps, branched peptidic molecules, from combinatorial libraries that bind to the carboxyl terminus of Ras and interfere with its farnesylation without inhibiting the farnesyl transferase. The active molecules were selected by a screening against the carboxy-terminal octapeptide of Ras. CONCLUSIONS: The implications of our findings are twofold. First, we demonstrate that it is possible to prevent enzymatic transformations by blocking the enzyme's access to its substrate using a synthetic small molecule to mask the substrate. Second, we show that it is feasible to derive molecules from combinatorial libraries that bind a specific epitope on a protein by selecting these molecules with the isolated peptide epitope.

Item Type: Paper
Uncontrolled Keywords: Alkyl and Aryl Transferases antagonists & inhibitors metabolism Amino Acid Sequence Epitopes/genetics Escherichia coli genetics metabolism Fluorescein Gene Library Genes, ras genetics Histamine metabolism Molecular Sequence Data Oncogene Proteins Fusion chemistry genetics ras Proteins metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > RAS
bioinformatics > genomics and proteomics > databases > databases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression > post-translational modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein characterization
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression
CSHL Authors:
Communities: CSHL labs > Wigler lab
Depositing User: CSHL Librarian
Date: March 1999
Date Deposited: 19 Apr 2012 14:49
Last Modified: 17 Nov 2016 16:57
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26175

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