NMR studies of novel inhibitors bound to farnesyl-protein transferase
| Autor: | J. Christopher Culberson, Steven M. Pitzenberger, Charles A. Omer, Michael J. Bogusky, Scott D. Mosser, Kenneth S. Koblan, S. Jane Desolms, E A Giuliani |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Farnesyl Protein Transferase Protein Conformation Stereochemistry Molecular Sequence Data Protein Prenylation Nuclear Overhauser effect Biochemistry Protein structure Prenylation Transferases Computer Graphics Humans Amino Acid Sequence Molecular Biology Alkyl and Aryl Transferases Molecular Structure Tetrapeptide Chemistry Nuclear magnetic resonance spectroscopy Ligand (biochemistry) Amides Recombinant Proteins Protein prenylation Oligopeptides Research Article Protein Binding |
| Zdroj: | Protein Science. 4:681-688 |
| ISSN: | 1469-896X 0961-8368 |
| DOI: | 10.1002/pro.5560040408 |
| Popis: | Farnesyl-protein transferase (FPTase) catalyzes the posttranslational farnesylation of the cysteine residue located in the carboxyl-terminal tetrapeptide of the Ras oncoprotein. Prenylation of this residue is essential for the membrane association and cell-transforming activities of ras. Inhibitors of FPTase have been demonstrated to inhibit ras-dependent cell transformation and thus represent a potential therapeutic strategy for the treatment of human cancers. The FPTase-bound conformation of a tetrapeptide inhibitor, CVWM, and a novel pseudopeptide inhibitor, L-739,787, have been determined by NMR spectroscopy. Distance constraints were derived from two-dimensional transferred nuclear Overhauser effect experiments. Ligand competition experiments identified the NOEs that originate from the active-site conformation. Structures were calculated with the combination of distance geometry and restrained energy minimization. Both peptide backbones are shown to adopt nonideal reverse-turn conformations most closely approximating a type III beta-turn. These results provide a basis for understanding the spatial arrangements necessary for inhibitor binding and selectivity and may aid in the design of therapeutic agents. |
| Databáze: | OpenAIRE |
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