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==Crystal structure of Trypanosome cruzi farnesyl diphosphate synthase in complex with [2-(n-propylamino)ethane-1,1-diyl]bisphosphonic acid and Mg2+== | ==Crystal structure of Trypanosome cruzi farnesyl diphosphate synthase in complex with [2-(n-propylamino)ethane-1,1-diyl]bisphosphonic acid and Mg2+== | ||
<StructureSection load='4dxj' size='340' side='right' caption='[[4dxj]], [[Resolution|resolution]] 2.35Å' scene=''> | <StructureSection load='4dxj' size='340' side='right'caption='[[4dxj]], [[Resolution|resolution]] 2.35Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4dxj]] is a 3 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4dxj]] is a 3 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=4DXJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DXJ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0M9:[2-(PROPYLAMINO)ETHANE-1,1-DIYL]BIS(PHOSPHONIC+ACID)'>0M9</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=IPE:3-METHYLBUT-3-ENYL+TRIHYDROGEN+DIPHOSPHATE'>IPE</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0M9:[2-(PROPYLAMINO)ETHANE-1,1-DIYL]BIS(PHOSPHONIC+ACID)'>0M9</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=IPE:3-METHYLBUT-3-ENYL+TRIHYDROGEN+DIPHOSPHATE'>IPE</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dxj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dxj OCA], [https://pdbe.org/4dxj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dxj RCSB], [https://www.ebi.ac.uk/pdbsum/4dxj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dxj ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/Q95WL3_TRYCR Q95WL3_TRYCR]] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 21: | Line 20: | ||
==See Also== | ==See Also== | ||
*[[Farnesyl diphosphate synthase|Farnesyl diphosphate synthase]] | *[[Farnesyl diphosphate synthase 3D structures|Farnesyl diphosphate synthase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Trypanosoma cruzi]] | ||
[[Category: | [[Category: Amzel LM]] | ||
[[Category: | [[Category: Aripirala S]] | ||
[[Category: | [[Category: Gabelli SB]] | ||
Revision as of 11:42, 21 September 2022
Crystal structure of Trypanosome cruzi farnesyl diphosphate synthase in complex with [2-(n-propylamino)ethane-1,1-diyl]bisphosphonic acid and Mg2+Crystal structure of Trypanosome cruzi farnesyl diphosphate synthase in complex with [2-(n-propylamino)ethane-1,1-diyl]bisphosphonic acid and Mg2+
Structural highlights
FunctionPublication Abstract from PubMedLinear 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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