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  • The EMBO Journal (2003) 22, 5963 - 5974
  • doi:10.1093/emboj/cdg571

Structure of mammalian protein geranylgeranyltransferase type-I

Jeffrey S. Taylor1, T. Scott Reid1, Kimberly L. Terry1, Patrick J. Casey2 and Lorena S. Beese1

  1. Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
  2. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA

Correspondence to:

Lorena S. Beese, E-mail: lsb@biochem.duke.edu

Received 20 January 2003; Accepted 18 September 2003; Revised 5 September 2003

Protein geranylgeranyltransferase type-I (GGTase-I), one of two CaaX prenyltransferases, is an essential enzyme in eukaryotes. GGTase-I catalyzes C-terminal lipidation of >100 proteins, including many GTP- binding regulatory proteins. We present the first structural information for mammalian GGTase-I, including a series of substrate and product complexes that delineate the path of the chemical reaction. These structures reveal that all protein prenyltransferases share a common reaction mechanism and identify specific residues that play a dominant role in determining prenyl group specificity. This hypothesis was confirmed by converting farnesyltransferase (15-C prenyl substrate) into GGTase-I (20-C prenyl substrate) with a single point mutation. GGTase-I discriminates against farnesyl diphosphate (FPP) at the product turnover step through the inability of a 15-C FPP to displace the 20-C prenyl-peptide product. Understanding these key features of specificity is expected to contribute to optimization of anti-cancer and anti-parasite drugs.

  • Keywords:

    • crystal structure,
    • G proteins,
    • lipid modification,
    • protein prenylation,
    • signal transduction