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2iej

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(New page: 200px<br /> <applet load="2iej" size="450" color="white" frame="true" align="right" spinBox="true" caption="2iej, resolution 1.800&Aring;" /> '''Human Protein Farn...)
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[[Image:2iej.gif|left|200px]]<br />
 
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<applet load="2iej" size="450" color="white" frame="true" align="right" spinBox="true"
 
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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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==Overview==
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==Human Protein Farnesyltransferase Complexed with Inhibitor Compound STN-48 And FPP Analog at 1.8A Resolution==
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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.
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<StructureSection load='2iej' size='340' side='right'caption='[[2iej]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2iej]] is a 2 chain structure with sequence from [https://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]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IEJ FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=FII:[(3,7,11-TRIMETHYL-DODECA-2,6,10-TRIENYLOXYCARBAMOYL)-METHYL]-PHOSPHONIC+ACID'>FII</scene>, <scene name='pdbligand=FRU:FRUCTOSE'>FRU</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PRD_900003:sucrose'>PRD_900003</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>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2iej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2iej OCA], [https://pdbe.org/2iej PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2iej RCSB], [https://www.ebi.ac.uk/pdbsum/2iej PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2iej ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/FNTA_HUMAN FNTA_HUMAN] Catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. The alpha subunit is thought to participate in a stable complex with the substrate. The beta subunit binds the peptide substrate. Through RAC1 prenylation and activation may positively regulate neuromuscular junction development downstream of MUSK (By similarity).
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ie/2iej_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2iej ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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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 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2IEJ OCA].
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*[[Farnesyltransferase 3D structures|Farnesyltransferase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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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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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein complex]]
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[[Category: Large Structures]]
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[[Category: Protein farnesyltransferase]]
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[[Category: Beese LS]]
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[[Category: Beese, L.S.]]
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[[Category: Hast MA]]
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[[Category: Hast, M.A.]]
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[[Category: ACT]]
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[[Category: FII]]
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[[Category: S48]]
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[[Category: SUC]]
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[[Category: ZN]]
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[[Category: caax]]
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[[Category: cancer]]
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[[Category: falciparum]]
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[[Category: farnesyl transferase]]
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[[Category: farnesyltransferase]]
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[[Category: ftase]]
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[[Category: lipid modification]]
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[[Category: malaria]]
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[[Category: plasmodium]]
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[[Category: protein prenylation]]
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[[Category: ras]]
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[[Category: stn-48]]
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[[Category: tumor regression]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:44:00 2007''
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Current revision

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

PDB ID 2iej

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