2iej

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[[Image:2iej.gif|left|200px]]<br /><applet load="2iej" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2iej.gif|left|200px]]
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caption="2iej, resolution 1.800&Aring;" />
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'''Human Protein Farnesyltransferase Complexed with Inhibitor Compound STN-48 And FPP Analog at 1.8A Resolution'''<br />
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{{Structure
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|PDB= 2iej |SIZE=350|CAPTION= <scene name='initialview01'>2iej</scene>, resolution 1.800&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=SUC:SUCROSE'>SUC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=S48:METHYL+N-{(3S)-1-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]-6-PHENYL-1,2,3,4-TETRAHYDROQUINOLIN-3-YL}-N-[(1-METHYL-1H-IMIDAZOL-4-YL)SULFONYL]GLYCINATE'>S48</scene> and <scene name='pdbligand=FII:[(3,7,11-TRIMETHYL-DODECA-2,6,10-TRIENYLOXYCARBAMOYL)-METHYL]-PHOSPHONIC ACID'>FII</scene>
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|ACTIVITY= [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]
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|GENE= FNTA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), FNTB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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}}
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'''Human Protein Farnesyltransferase Complexed with Inhibitor Compound STN-48 And FPP Analog at 1.8A Resolution'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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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].
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2IEJ is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IEJ OCA].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17208314 17208314]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/17208314 17208314]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
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[[Category: plasmodium]]
[[Category: plasmodium]]
[[Category: protein prenylation]]
[[Category: protein prenylation]]
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[[Category: ras]]
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[[Category: ra]]
[[Category: stn-48]]
[[Category: stn-48]]
[[Category: tumor regression]]
[[Category: tumor regression]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:51:49 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:28:38 2008''

Revision as of 15:28, 20 March 2008

Image:2iej.gif


PDB ID 2iej

Drag the structure with the mouse to rotate
, resolution 1.800Å
Ligands: , , , and
Gene: FNTA (Homo sapiens), FNTB (Homo sapiens)
Activity: Protein farnesyltransferase, with EC number 2.5.1.58
Coordinates: save as pdb, mmCIF, xml



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. 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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