1kzo

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spinqualitylabelsall models 1kzo, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH FARNESYLATED K-RAS4B PEPTIDE PRODUCT AND FARNESYL DIPHOSPHATE SUBSTRATE BOUND SIMULTANEOUSLY

Overview

Protein farnesyltransferase (FTase) catalyses the attachment of a farnesyl, lipid group to numerous essential signal transduction proteins, including, members of the Ras superfamily. The farnesylation of Ras oncoproteins, which are associated with 30% of human cancers, is essential for their, transforming activity. FTase inhibitors are currently in clinical trials, for the treatment of cancer. 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.

About this Structure

1KZO is a Protein complex structure of sequences from Rattus norvegicus with ZN, FAR, FPP and ACY as ligands. Active as Squalene synthase, with EC number 2.5.1.21 Full crystallographic information is available from OCA.

Reference

Reaction path of protein farnesyltransferase at atomic resolution., Long SB, Casey PJ, Beese LS, Nature. 2002 Oct 10;419(6907):645-50. PMID:12374986

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