4k10

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==Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM and Mg2+==
==Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM and Mg2+==
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<StructureSection load='4k10' size='340' side='right' caption='[[4k10]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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<StructureSection load='4k10' size='340' side='right'caption='[[4k10]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4k10]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Leima Leima]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K10 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K10 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4k10]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_major Leishmania major]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K10 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K10 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=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NI9:3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM'>NI9</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2.3&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jzb|4jzb]], [[4jzx|4jzx]]</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=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NI9:3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM'>NI9</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FPPS, LMJF_22_1360 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5664 LEIMA])</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=4k10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k10 OCA], [https://pdbe.org/4k10 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k10 RCSB], [https://www.ebi.ac.uk/pdbsum/4k10 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k10 ProSAT]</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=4k10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k10 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4k10 RCSB], [http://www.ebi.ac.uk/pdbsum/4k10 PDBsum]</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/Q4QBL1_LEIMA Q4QBL1_LEIMA]
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Farnesyl diphosphate synthase (FPPS) is an essential enzyme involved in the biosynthesis of sterols (cholesterol in humans and ergosterol in yeasts, fungi and trypanosomatid parasites) as well as in protein prenylation. It is inhibited by bisphosphonates, a class of drugs used in humans to treat diverse bone-related diseases. The development of bisphosphonates as antiparasitic compounds targeting ergosterol biosynthesis has become an important route for therapeutic intervention. Here, the X-ray crystallographic structures of complexes of FPPS from Leishmania major (the causative agent of cutaneous leishmaniasis) with three bisphosphonates determined at resolutions of 1.8, 1.9 and 2.3 A are reported. Two of the inhibitors, 1-(2-hydroxy-2,2-diphosphonoethyl)-3-phenylpyridinium (300B) and 3-butyl-1-(2,2-diphosphonoethyl)pyridinium (476A), co-crystallize with the homoallylic substrate isopentenyl diphosphate (IPP) and three Ca(2+) ions. A third inhibitor, 3-fluoro-1-(2-hydroxy-2,2-diphosphonoethyl)pyridinium (46I), was found to bind two Mg(2+) ions but not IPP. Calorimetric studies showed that binding of the inhibitors is entropically driven. Comparison of the structures of L. major FPPS (LmFPPS) and human FPPS provides new information for the design of bisphosphonates that will be more specific for inhibition of LmFPPS. The asymmetric structure of the LmFPPS-46I homodimer indicates that binding of the allylic substrate to both monomers of the dimer results in an asymmetric dimer with one open and one closed homoallylic site. It is proposed that IPP first binds to the open site, which then closes, opening the site on the other monomer, which closes after binding the second IPP, leading to the symmetric fully occupied FPPS dimer observed in other structures.
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Structural and thermodynamic basis of the inhibition of Leishmania major farnesyl diphosphate synthase by nitrogen-containing bisphosphonates.,Aripirala S, Gonzalez-Pacanowska D, Oldfield E, Kaiser M, Amzel LM, Gabelli SB Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):802-10. doi:, 10.1107/S1399004713033221. Epub 2014 Feb 22. PMID:24598749<ref>PMID:24598749</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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==See Also==
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</div>
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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: Leima]]
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[[Category: Large Structures]]
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[[Category: Amzel, L M]]
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[[Category: Leishmania major]]
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[[Category: Aripirala, S]]
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[[Category: Amzel LM]]
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[[Category: Gabelli, S]]
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[[Category: Aripirala S]]
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[[Category: Farnesyl diphosphate synthase]]
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[[Category: Gabelli S]]
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[[Category: Farnesyl pyrophosphate synthase]]
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[[Category: Fpp]]
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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 Leshmaniasis major Farnesyl diphosphate synthase in complex with 3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM and Mg2+

PDB ID 4k10

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