1. Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA

Correspondence to: Lorena S. Beese Correspondence and requests for materials should be addressed to L.S.B (e-mail: Email: lsb@biochem.duke.edu). The coordinates for the complexes with farnesylated product and with both FPP and product, as well as the transition state model have been deposited in the Protein Data Bank (Research Collaboratory for Structural Bioinformatics), PDB ID numbers 1KZP, 1KZO and 1KZR, respectively.

Abstract

Protein farnesyltransferase (FTase) catalyses the attachment of a farnesyl lipid group to numerous essential signal transduction proteins, including members of the Ras superfamily¹. The farnesylation of Ras oncoproteins, which are associated with 30% of human cancers, is essential for their transforming activity². FTase inhibitors are currently in clinical trials for the treatment of cancer^{2, 3, 4}. Here we present a complete series of structures representing the major steps along the reaction coordinate of this enzyme. From these observations can be deduced the determinants of substrate specificity and an unusual mechanism in which product release requires binding of substrate, analogous to classically processive enzymes. A structural model for the transition state consistent with previous mechanistic studies was also constructed. The processive nature of the reaction suggests the structural basis for the successive addition of two prenyl groups to Rab proteins by the homologous enzyme geranylgeranyltransferase type-II. Finally, known FTase inhibitors seem to differ in their mechanism of inhibiting the enzyme.