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4e1e

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==Crystal structure of Trypanosome cruzi farnesyl diphosphate synthase in complex with [2-(n-hexylamino)ethane-1,1-diyl]bisphosphonic acid and Mg2+==
==Crystal structure of Trypanosome cruzi farnesyl diphosphate synthase in complex with [2-(n-hexylamino)ethane-1,1-diyl]bisphosphonic acid and Mg2+==
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<StructureSection load='4e1e' size='340' side='right' caption='[[4e1e]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
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<StructureSection load='4e1e' size='340' side='right'caption='[[4e1e]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4e1e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Trycr Trycr]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E1E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E1E FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4e1e]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_cruzi Trypanosoma cruzi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E1E FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MW:[2-(HEXYLAMINO)ETHANE-1,1-DIYL]BIS(PHOSPHONIC+ACID)'>0MW</scene>, <scene name='pdbligand=IPE:3-METHYLBUT-3-ENYL+TRIHYDROGEN+DIPHOSPHATE'>IPE</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
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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]] 2.65&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1yhk|1yhk]], [[1yhl|1yhl]], [[1yhm|1yhm]], [[3iba|3iba]], [[3ick|3ick]], [[3icm|3icm]], [[3icn|3icn]], [[3icz|3icz]], [[4dwb|4dwb]], [[4dwg|4dwg]], [[4dxj|4dxj]], [[4dzw|4dzw]]</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=0MW:[2-(HEXYLAMINO)ETHANE-1,1-DIYL]BIS(PHOSPHONIC+ACID)'>0MW</scene>, <scene name='pdbligand=IPE:3-METHYLBUT-3-ENYL+TRIHYDROGEN+DIPHOSPHATE'>IPE</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FPPS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5693 TRYCR])</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=4e1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e1e OCA], [https://pdbe.org/4e1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e1e RCSB], [https://www.ebi.ac.uk/pdbsum/4e1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e1e ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/(2E,6E)-farnesyl_diphosphate_synthase (2E,6E)-farnesyl diphosphate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.10 2.5.1.10] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e1e OCA], [http://pdbe.org/4e1e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4e1e RCSB], [http://www.ebi.ac.uk/pdbsum/4e1e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4e1e ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/Q95WL3_TRYCR Q95WL3_TRYCR]
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Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi , the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC(50) values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitors bind to the allylic site of the enzyme, with their alkyl chain occupying the cavity that binds the isoprenoid chain of the substrate. The compounds bind to TcFPPS with unfavorable enthalpy compensated by a favorable entropy that results from a delicate balance between two opposing effects: the loss of conformational entropy due to freezing of single bond rotations and the favorable burial of the hydrophobic alkyl chains. The data suggest that introduction of strategically placed double bonds and methyl branches should increase affinity substantially.
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Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase.,Aripirala S, Szajnman SH, Jakoncic J, Rodriguez JB, Docampo R, Gabelli SB, Amzel LM J Med Chem. 2012 Jul 26;55(14):6445-54. Epub 2012 Jul 5. PMID:22715997<ref>PMID:22715997</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4e1e" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Farnesyl diphosphate synthase|Farnesyl diphosphate synthase]]
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*[[Farnesyl diphosphate synthase 3D structures|Farnesyl diphosphate synthase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Trycr]]
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[[Category: Large Structures]]
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[[Category: Amzel, L M]]
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[[Category: Trypanosoma cruzi]]
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[[Category: Aripirala, S]]
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[[Category: Amzel LM]]
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[[Category: Gabelli, S B]]
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[[Category: Aripirala S]]
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[[Category: Farnesyl pyrophosphate synthase]]
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[[Category: Gabelli SB]]
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[[Category: Geranyl transferase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Crystal structure of Trypanosome cruzi farnesyl diphosphate synthase in complex with [2-(n-hexylamino)ethane-1,1-diyl]bisphosphonic acid and Mg2+

PDB ID 4e1e

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