2iej
From Proteopedia
(New page: 200px<br /> <applet load="2iej" size="450" color="white" frame="true" align="right" spinBox="true" caption="2iej, resolution 1.800Å" /> '''Human Protein Farn...) |
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| - | [[Image:2iej.gif|left|200px]]<br /> | + | [[Image:2iej.gif|left|200px]]<br /><applet load="2iej" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2iej" size=" | + | |
caption="2iej, resolution 1.800Å" /> | caption="2iej, resolution 1.800Å" /> | ||
'''Human Protein Farnesyltransferase Complexed with Inhibitor Compound STN-48 And FPP Analog at 1.8A Resolution'''<br /> | '''Human Protein Farnesyltransferase Complexed with Inhibitor Compound STN-48 And FPP Analog at 1.8A Resolution'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The post-translational farnesylation of proteins serves to anchor a subset | + | 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== | ==About this Structure== | ||
| - | 2IEJ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SUC, ZN, ACT, S48 and FII as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Protein_farnesyltransferase Protein farnesyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.58 2.5.1.58] Full crystallographic information is available from [http:// | + | 2IEJ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SUC:'>SUC</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=S48:'>S48</scene> and <scene name='pdbligand=FII:'>FII</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Protein_farnesyltransferase Protein farnesyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.58 2.5.1.58] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IEJ OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Protein farnesyltransferase]] | [[Category: Protein farnesyltransferase]] | ||
| - | [[Category: Beese, L | + | [[Category: Beese, L S.]] |
| - | [[Category: Hast, M | + | [[Category: Hast, M A.]] |
[[Category: ACT]] | [[Category: ACT]] | ||
[[Category: FII]] | [[Category: FII]] | ||
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[[Category: tumor regression]] | [[Category: tumor regression]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:51:49 2008'' |
Revision as of 15:51, 21 February 2008
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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 , , , and 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
Page seeded by OCA on Thu Feb 21 17:51:49 2008
Categories: Homo sapiens | Protein complex | Protein farnesyltransferase | Beese, L S. | Hast, M A. | ACT | FII | S48 | SUC | ZN | Caax | Cancer | Falciparum | Farnesyl transferase | Farnesyltransferase | Ftase | Lipid modification | Malaria | Plasmodium | Protein prenylation | Ras | Stn-48 | Tumor regression
