4jzb: Difference between revisions
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==Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)-3-PHENYLPYRIDINIUM, IPP and Ca2+== | ==Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)-3-PHENYLPYRIDINIUM, IPP and Ca2+== | ||
<StructureSection load='4jzb' size='340' side='right' caption='[[4jzb]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='4jzb' size='340' side='right'caption='[[4jzb]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4jzb]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4jzb]] is a 2 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=4JZB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JZB FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=IPE:3-METHYLBUT-3-ENYL+TRIHYDROGEN+DIPHOSPHATE'>IPE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=P2H:1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)-3-PHENYLPYRIDINIUM'>P2H</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=FME:N-FORMYLMETHIONINE'>FME</scene>, <scene name='pdbligand=IPE:3-METHYLBUT-3-ENYL+TRIHYDROGEN+DIPHOSPHATE'>IPE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=P2H:1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)-3-PHENYLPYRIDINIUM'>P2H</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=4jzb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jzb OCA], [https://pdbe.org/4jzb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jzb RCSB], [https://www.ebi.ac.uk/pdbsum/4jzb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jzb 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/Q4QBL1_LEIMA Q4QBL1_LEIMA] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 4jzb" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4jzb" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Farnesyl diphosphate synthase 3D structures|Farnesyl diphosphate synthase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Leishmania major]] | ||
[[Category: | [[Category: Amzel LM]] | ||
[[Category: | [[Category: Aripirala S]] | ||
[[Category: | [[Category: Gabelli S]] | ||
Latest revision as of 11:24, 9 October 2024
Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)-3-PHENYLPYRIDINIUM, IPP and Ca2+Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)-3-PHENYLPYRIDINIUM, IPP and Ca2+
Structural highlights
FunctionPublication Abstract from PubMedFarnesyl 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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