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| - | [[Image:2r2l.jpg|left|200px]] | |
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| - | {{Structure
| + | ==Structure of Farnesyl Protein Transferase bound to PB-93== |
| - | |PDB= 2r2l |SIZE=350|CAPTION= <scene name='initialview01'>2r2l</scene>, resolution 2.230Å
| + | <StructureSection load='2r2l' size='340' side='right'caption='[[2r2l]], [[Resolution|resolution]] 2.23Å' scene=''> |
| - | |SITE= <scene name='pdbsite=AC1:Zn+Binding+Site+For+Residue+B+1'>AC1</scene>, <scene name='pdbsite=AC2:Fpp+Binding+Site+For+Residue+B+424'>AC2</scene> and <scene name='pdbsite=AC3:Pb9+Binding+Site+For+Residue+B+425'>AC3</scene>
| + | == Structural highlights == |
| - | |LIGAND= <scene name='pdbligand=FPP:FARNESYL+DIPHOSPHATE'>FPP</scene>, <scene name='pdbligand=PB9:METHYL+4-{[{(3S)-6-CYANO-1-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]-1,2,3,4-TETRAHYDROQUINOLIN-3-YL}(PYRIDIN-2-YLSULFONYL)AMINO]METHYL}PIPERIDINE-1-CARBOXYLATE'>PB9</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> | + | <table><tr><td colspan='2'>[[2r2l]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R2L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2R2L FirstGlance]. <br> |
| - | |ACTIVITY= <span class='plainlinks'>[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] </span>
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.23Å</td></tr> |
| - | |GENE= Fnta ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus]), Fntb ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus])
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FPP:FARNESYL+DIPHOSPHATE'>FPP</scene>, <scene name='pdbligand=PB9:METHYL+4-{[{(3S)-6-CYANO-1-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]-1,2,3,4-TETRAHYDROQUINOLIN-3-YL}(PYRIDIN-2-YLSULFONYL)AMINO]METHYL}PIPERIDINE-1-CARBOXYLATE'>PB9</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | |DOMAIN=
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2r2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r2l OCA], [https://pdbe.org/2r2l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2r2l RCSB], [https://www.ebi.ac.uk/pdbsum/2r2l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2r2l ProSAT]</span></td></tr> |
| - | |RELATEDENTRY=
| + | </table> |
| - | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r2l OCA], [http://www.ebi.ac.uk/pdbsum/2r2l PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2r2l RCSB]</span>
| + | == Function == |
| - | }}
| + | [https://www.uniprot.org/uniprot/FNTA_RAT FNTA_RAT] 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). |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r2/2r2l_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </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=2r2l ConSurf]. |
| | + | <div style="clear:both"></div> |
| | | | |
| - | '''Structure of Farnesyl Protein Transferase bound to PB-93'''
| + | ==See Also== |
| - | | + | *[[Farnesyltransferase 3D structures|Farnesyltransferase 3D structures]] |
| - | | + | __TOC__ |
| - | ==Overview== | + | </StructureSection> |
| - | New antimalarials are urgently needed. We have shown that tetrahydroquinoline (THQ) protein farnesyltransferase (PFT) inhibitors (PFTIs) are effective against the Plasmodium falciparum PFT and are effective at killing P. falciparum in vitro. Previously described THQ PFTIs had limitations of poor oral bioavailability and rapid clearance from the circulation of rodents. In this paper, we validate both the Caco-2 cell permeability model for predicting THQ intestinal absorption and the in vitro liver microsome model for predicting THQ clearance in vivo. Incremental improvements in efficacy, oral absorption, and clearance rate were monitored by in vitro tests; and these tests were followed up with in vivo absorption, distribution, metabolism, and excretion studies. One compound, PB-93, achieved cure when it was given orally to P. berghei-infected rats every 8 h for a total of 72 h. However, PB-93 was rapidly cleared, and dosing every 12 h failed to cure the rats. Thus, the in vivo results corroborate the in vitro pharmacodynamics and demonstrate that 72 h of continuous high-level exposure to PFTIs is necessary to kill plasmodia. The metabolism of PB-93 was demonstrated by a novel technique that relied on double labeling with a radiolabel and heavy isotopes combined with radiometric liquid chromatography and mass spectrometry. The major liver microsome metabolite of PB-93 has the PFT Zn-binding N-methyl-imidazole removed; this metabolite is inactive in blocking PFT function. By solving the X-ray crystal structure of PB-93 bound to rat PFT, a model of PB-93 bound to malarial PFT was constructed. This model suggests areas of the THQ PFTIs that can be modified to retain efficacy and protect the Zn-binding N-methyl-imidazole from dealkylation.
| + | [[Category: Large Structures]] |
| - | | + | |
| - | ==About this Structure==
| + | |
| - | 2R2L is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R2L OCA].
| + | |
| - | | + | |
| - | ==Reference==
| + | |
| - | Efficacy, pharmacokinetics, and metabolism of tetrahydroquinoline inhibitors of Plasmodium falciparum protein farnesyltransferase., Van Voorhis WC, Rivas KL, Bendale P, Nallan L, Horney C, Barrett LK, Bauer KD, Smart BP, Ankala S, Hucke O, Verlinde CL, Chakrabarti D, Strickland C, Yokoyama K, Buckner FS, Hamilton AD, Williams DK, Lombardo LJ, Floyd D, Gelb MH, Antimicrob Agents Chemother. 2007 Oct;51(10):3659-71. Epub 2007 Jul 2. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17606674 17606674]
| + | |
| - | [[Category: Protein complex]]
| + | |
| - | [[Category: Protein farnesyltransferase]] | + | |
| | [[Category: Rattus norvegicus]] | | [[Category: Rattus norvegicus]] |
| - | [[Category: Strickland, C O.]] | + | [[Category: Strickland CO]] |
| - | [[Category: Voorhis, W.]] | + | [[Category: Voorhis W]] |
| - | [[Category: fpt]]
| + | |
| - | [[Category: malaria]]
| + | |
| - | [[Category: metal-binding]]
| + | |
| - | [[Category: phosphorylation]]
| + | |
| - | [[Category: prenyltransferase]]
| + | |
| - | [[Category: transferase]]
| + | |
| - | [[Category: zinc]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:55:52 2008''
| + | |
