Conformation of a Heptapeptide Substrate Bound to Protein Farnesyltransferase

Sarah J. Stradley, Josep Rizo, Lila M. Gierasch

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Protein farnesyltransferase catalyzes isoprenylation of the cysteine four residues from the C-terminus of several proteins including p21ras. Farnesylation is required for the transforming activity of Ras, and many efforts are underway to develop inhibitors of farnesyltransferase. We have used nuclear magnetic resonance spectroscopy to determine the farnesyltransferase-bound conformation of a heptapeptide substrate, KTKCVFM, which competes for the modification of p21Ha-ras in an in vitro assay. Analysis of transferred nuclear Overhauser effects reveals that the CVFM sequence of the peptide substrate is directly involved in binding to the enzyme and adopts a type I β-turn conformation in the bound state. The present structural information should aid in the design of more effective inhibitors of the enzyme and in understanding the nature of the peptide binding site.

Original languageEnglish (US)
Pages (from-to)12586-12590
Number of pages5
JournalBiochemistry
Volume32
Issue number47
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Biochemistry

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