2iej

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spinqualitylabelsall models 2iej, resolution 1.800Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Human Protein Farnesyltransferase Complexed with Inhibitor Compound STN-48 And FPP Analog at 1.8A Resolution

Overview

The post-translational farnesylation of proteins serves to anchor a subset, of intracellular proteins to membranes in eukaryotic organisms and also, promotes protein-protein interactions. This enzymatic reaction is carried, out by protein farnesyltransferase (PFT), which catalyzes the transfer of, a 15-carbon isoprenoid lipid unit, a farnesyl group, from farnesyl, pyrophosphate to the C-termini of proteins containing a CaaX motif., Inhibition of PFT is lethal to the pathogenic protozoa Plasmodium, falciparum. Previously, we have shown that parasites resistant to a, tetrahydroquinoline (THQ)-based PFT inhibitor BMS-388891 have mutations, leading to amino acid substitutions in PFT that map to the peptide, substrate binding domain. We now report the selection of parasites, resistant to another THQ PFT inhibitor BMS-339941. In whole cell assays, sensitivity to BMS-339941 was reduced by 33-fold in a resistant clone, and, biochemical analysis demonstrated a corresponding 33-fold increase in the, BMS-339941 K(i) for the mutant PFT enzyme. More detailed kinetic analysis, revealed that the mutant enzyme required higher concentration of peptide, and farnesyl pyrophosphate substrates for optimum catalysis. Unlike, previously characterized parasites resistant to BMS-388891, the resistant, parasites have a mutation which is predicted to be in a distinct location, of the enzymatic pocket, near the farnesyl pyrophosphate binding pocket., This is the first description of a mutation from any species affecting the, farnesyl pyrophosphate binding pocket with reduced efficacy of PFT, inhibitors. These data provide further support that PFT is the target of, THQ inhibitors in P. falciparum and suggest that PFT inhibitors should be, combined with other antimalarial agents to minimize the development of, resistant parasites.

About this Structure

2IEJ is a Protein complex structure of sequences from Homo sapiens with SUC, ZN, ACT, S48 and FII as ligands. Active as Protein farnesyltransferase, with EC number 2.5.1.58 Full crystallographic information is available from OCA.

Reference

Resistance mutations at the lipid substrate binding site of Plasmodium falciparum protein farnesyltransferase., Eastman RT, White J, Hucke O, Yokoyama K, Verlinde CL, Hast MA, Beese LS, Gelb MH, Rathod PK, Van Voorhis WC, Mol Biochem Parasitol. 2007 Mar;152(1):66-71. Epub 2006 Dec 22. PMID:17208314

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