1sa5

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spinqualitylabelsall models 1sa5, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Rat protein farnesyltransferase complexed with FPP and BMS-214662

Overview

The search for new cancer therapeutics has identified protein farnesyltransferase (FTase) as a promising drug target. This enzyme attaches isoprenoid lipids to signal transduction proteins involved in growth and differentiation. The two FTase inhibitors (FTIs), R115777 (tipifarnib/Zarnestra) and BMS-214662, have undergone evaluation as cancer therapeutics in phase I and II clinical trials. R115777 has been evaluated in phase III clinical trials and shows indications for the treatment of blood and breast malignancies. Here we present crystal structures of R115777 and BMS-214662 complexed with mammalian FTase. These structures illustrate the molecular mechanism of inhibition and selectivity toward FTase over the related enzyme, protein geranylgeranyltransferase type I (GGTase-I). These results, combined with previous biochemical and structural analyses, identify features of FTase that could be exploited to modulate inhibitor potency and specificity and should aid in the continued development of FTIs as therapeutics for the treatment of cancer and parasitic infections.

About this Structure

1SA5 is a Protein complex structure of sequences from Rattus norvegicus with , , and as ligands. Active as Protein farnesyltransferase, with EC number 2.5.1.58 Full crystallographic information is available from OCA.

Reference

Crystal structures of the anticancer clinical candidates R115777 (Tipifarnib) and BMS-214662 complexed with protein farnesyltransferase suggest a mechanism of FTI selectivity., Reid TS, Beese LS, Biochemistry. 2004 Jun 8;43(22):6877-84. PMID:15170324

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