2IEJ

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

2IEJ の概要

• エントリーDOI: 10.2210/pdb2iej/pdb
• 関連するBIRD辞書のPRD_ID: PRD_900003
• 分子名称: Protein farnesyltransferase/geranylgeranyltransferase type I alpha subunit, Protein farnesyltransferase subunit beta, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, ... (8 entities in total)
• 機能のキーワード: ftase, farnesyltransferase, farnesyl transferase, caax, ras, cancer, tumor regression, stn-48, protein prenylation, lipid modification, plasmodium, falciparum, malaria, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 95284.20

構造登録者

Hast, M.A.,Beese, L.S. (登録日: 2006-09-19, 公開日: 2007-01-23, 最終更新日: 2024-02-21)

主引用文献

Eastman, R.T.,White, J.,Hucke, O.,Yokoyama, K.,Verlinde, C.L.,Hast, M.A.,Beese, L.S.,Gelb, M.H.,Rathod, P.K.,Van Voorhis, W.C.
Resistance mutations at the lipid substrate binding site of Plasmodium falciparum protein farnesyltransferase.
Mol.Biochem.Parasitol., 152:66-71, 2007

PubMed Abstract: 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.

PubMed: 17208314
DOI: 10.1016/j.molbiopara.2006.11.012

実験手法

X-RAY DIFFRACTION (1.8 Å)