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| | <StructureSection load='6mso' size='340' side='right'caption='[[6mso]], [[Resolution|resolution]] 2.05Å' scene=''> | | <StructureSection load='6mso' size='340' side='right'caption='[[6mso]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6mso]] 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=6MSO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MSO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6mso]] 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=6MSO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MSO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JYD:(2S)-2-sulfanylbutanedioic+acid'>JYD</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.053Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LMJF_24_0320 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5664 LEIMA])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JYD:(2S)-2-sulfanylbutanedioic+acid'>JYD</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Fumarate_hydratase Fumarate hydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.2 4.2.1.2] </span></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=6mso FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mso OCA], [https://pdbe.org/6mso PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mso RCSB], [https://www.ebi.ac.uk/pdbsum/6mso PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mso ProSAT]</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=6mso FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mso OCA], [http://pdbe.org/6mso PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mso RCSB], [http://www.ebi.ac.uk/pdbsum/6mso PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mso ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/FUM1_LEIMA FUM1_LEIMA] Catalyzes the reversible hydration of fumarate to (S)-malate (PubMed:22569531, PubMed:30645090). Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a transition step in the production of energy in the form of NADH (Probable).<ref>PMID:22569531</ref> <ref>PMID:30645090</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Fumarate hydratase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Leima]] | + | [[Category: Leishmania major]] |
| - | [[Category: Drennan, C L]] | + | [[Category: Drennan CL]] |
| - | [[Category: Feliciano, P R]] | + | [[Category: Feliciano PR]] |
| - | [[Category: Nonato, M C]] | + | [[Category: Nonato MC]] |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Lyase]]
| + | |
| - | [[Category: Lyase-lyase inhibitor complex]]
| + | |
| - | [[Category: Mitochondrial]]
| + | |
| Structural highlights
Function
FUM1_LEIMA Catalyzes the reversible hydration of fumarate to (S)-malate (PubMed:22569531, PubMed:30645090). Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a transition step in the production of energy in the form of NADH (Probable).[1] [2]
Publication Abstract from PubMed
Leishmaniases affect the poorest people on earth and have no effective drug therapy. Here, we present the crystal structure of the mitochondrial isoform of class I fumarate hydratase (FH) from Leishmania major and compare it to the previously determined cytosolic Leishmania major isoform. We further describe the mechanism of action of the first class-specific FH inhibitor, 2-thiomalate, through X-ray crystallography and inhibition assays. Our crystal structures of both FH isoforms with inhibitor bound at 2.05 A resolution and 1.60 A resolution show high structural similarity. These structures further reveal that the selectivity of 2-thiomalate for class I FHs is due to direct coordination of the inhibitor to the unique Fe of the catalytic [4Fe-4S] cluster that is found in class I parasitic FHs but is absent from class II human FH. These studies provide the structural scaffold in order to exploit class I FHs as potential drug targets against leishmaniases as well as Chagas diseases, sleeping sickness and malaria.
Crystal structures of fumarate hydratases from Leishmania major in a complex with inhibitor 2-thiomalate.,Feliciano PR, Drennan CL, Nonato MC ACS Chem Biol. 2019 Jan 15. doi: 10.1021/acschembio.8b00972. PMID:30645090[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Feliciano PR, Gupta S, Dyszy F, Dias-Baruffi M, Costa-Filho AJ, Michels PA, Nonato MC. Fumarate hydratase isoforms of Leishmania major: subcellular localization, structural and kinetic properties. Int J Biol Macromol. 2012 Jul-Aug;51(1-2):25-31. PMID:22569531 doi:10.1016/j.ijbiomac.2012.04.025
- ↑ Feliciano PR, Drennan CL, Nonato MC. Crystal structures of fumarate hydratases from Leishmania major in a complex with inhibitor 2-thiomalate. ACS Chem Biol. 2019 Jan 15. doi: 10.1021/acschembio.8b00972. PMID:30645090 doi:http://dx.doi.org/10.1021/acschembio.8b00972
- ↑ Feliciano PR, Drennan CL, Nonato MC. Crystal structures of fumarate hydratases from Leishmania major in a complex with inhibitor 2-thiomalate. ACS Chem Biol. 2019 Jan 15. doi: 10.1021/acschembio.8b00972. PMID:30645090 doi:http://dx.doi.org/10.1021/acschembio.8b00972
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