6mso: Difference between revisions

Revision as of 06:38, 11 October 2023

Crystal structure of mitochondrial fumarate hydratase from Leishmania major in a complex with inhibitor thiomalate

Structural highlights

6mso is a 4 chain structure with sequence from Leishmania major. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.053Å
Ligands:	1PE, GOL, JYD, SF4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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:https://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:https://dx.doi.org/10.1021/acschembio.8b00972

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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:https://dx.doi.org/10.1021/acschembio.8b00972

[3] 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:https://dx.doi.org/10.1021/acschembio.8b00972

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='6mso' size='340' side='right'caption='[[6mso]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
 == 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]] 2.053&#8491;</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>
+== 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;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Fumarate hydratase]]
 [[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]]

6mso: Difference between revisions

Revision as of 06:38, 11 October 2023

Crystal structure of mitochondrial fumarate hydratase from Leishmania major in a complex with inhibitor thiomalate

Structural highlights

Function

Publication Abstract from PubMed

References

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