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4k10

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Revision as of 18:35, 11 August 2016

Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM and Mg2+

Structural highlights

4k10 is a 4 chain structure with sequence from Leima. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , ,
Related:	4jzb, 4jzx
Gene:	FPPS, LMJF_22_1360 (LEIMA)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

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.

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.

References

↑ Aripirala S, Gonzalez-Pacanowska D, Oldfield E, Kaiser M, Amzel LM, Gabelli SB. Structural and thermodynamic basis of the inhibition of Leishmania major farnesyl diphosphate synthase by nitrogen-containing bisphosphonates. Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):802-10. doi:, 10.1107/S1399004713033221. Epub 2014 Feb 22. PMID:24598749 doi:http://dx.doi.org/10.1107/S1399004713033221

1 Structural highlights
2 Publication Abstract from PubMed
3 References

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Retrieved from "http://52.214.119.220/wiki/index.php/4k10"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM and Mg2+==
 <StructureSection load='4k10' size='340' side='right' caption='[[4k10]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jzb|4jzb]], [[4jzx|4jzx]]</td></tr>
 <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>
-<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>
+<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://pdbe.org/4k10 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4k10 RCSB], [http://www.ebi.ac.uk/pdbsum/4k10 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4k10 ProSAT]</span></td></tr>
 </table>
 <div style="background-color:#fffaf0;">
@@ Line 16: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4k10" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4k10

From Proteopedia

Revision as of 18:35, 11 August 2016

Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM and Mg2+

Structural highlights

Publication Abstract from PubMed

References

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