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Reaction path of protein farnesyltransferase at atomic resolution


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 cancer2,3,4. 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.

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Figure 1: Structures along the FTase reaction path.
Figure 2: Comparison of reactant and product conformations and a proposed model for the transition state.
Figure 3: Farnesylated peptide product conformations at the active site (stereo).
Figure 4: A model for processive prenylation catalysed by GGTase-II (stereo).


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We thank H. W. Hellinga for extensive discussions and K. L. Terry for assistance with crystallization and data collection. The work was supported by National Institutes of Health grants to L.S.B. and P.J.C., and an American Heart Association predoctoral fellowship to S.B.L.

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Correspondence to Lorena S. Beese.

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Long, S., Casey, P. & Beese, L. Reaction path of protein farnesyltransferase at atomic resolution. Nature 419, 645–650 (2002).

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