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| | ==Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate== | | ==Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate== |
| - | <StructureSection load='3hbb' size='340' side='right' caption='[[3hbb]], [[Resolution|resolution]] 3.00Å' scene=''> | + | <StructureSection load='3hbb' size='340' side='right'caption='[[3hbb]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3hbb]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trycr Trycr]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HBB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3HBB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3hbb]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_cruzi Trypanosoma cruzi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HBB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HBB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TMQ:TRIMETREXATE'>TMQ</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]] 3Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3clb|3clb]], [[3cl9|3cl9]], [[2h2q|2h2q]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TMQ:TRIMETREXATE'>TMQ</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dhfr-ts ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5693 TRYCR])</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=3hbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hbb OCA], [https://pdbe.org/3hbb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hbb RCSB], [https://www.ebi.ac.uk/pdbsum/3hbb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hbb 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=3hbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hbb OCA], [http://pdbe.org/3hbb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3hbb RCSB], [http://www.ebi.ac.uk/pdbsum/3hbb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3hbb ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/Q8T5T8_TRYCR Q8T5T8_TRYCR]] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389] | + | [https://www.uniprot.org/uniprot/DRTS_TRYCR DRTS_TRYCR] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.[HAMAP-Rule:MF_00008] |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Dihydrofolate reductase|Dihydrofolate reductase]] | + | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Trycr]] | + | [[Category: Large Structures]] |
| - | [[Category: Chattopadhyay, D]] | + | [[Category: Trypanosoma cruzi]] |
| - | [[Category: Schormann, N]] | + | [[Category: Chattopadhyay D]] |
| - | [[Category: Senkovich, O]] | + | [[Category: Schormann N]] |
| - | [[Category: Bifunctional enzyme in complex with nadp and tmq]] | + | [[Category: Senkovich O]] |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
DRTS_TRYCR Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.[HAMAP-Rule:MF_00008]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The flagellate protozoan parasite Trypanosoma cruzi is the pathogenic agent of Chagas disease (also called American trypanosomiasis), which causes approximately 50,000 deaths annually. The disease is endemic in South and Central America. The parasite is usually transmitted by a blood-feeding insect vector, but can also be transmitted via blood transfusion. In the chronic form, Chagas disease causes severe damage to the heart and other organs. There is no satisfactory treatment for chronic Chagas disease and no vaccine is available. There is an urgent need for the development of chemotherapeutic agents for the treatment of T. cruzi infection and therefore for the identification of potential drug targets. The dihydrofolate reductase activity of T. cruzi, which is expressed as part of a bifunctional enzyme, dihydrofolate reductase-thymidylate synthase (DHFR-TS), is a potential target for drug development. In order to gain a detailed understanding of the structure-function relationship of T. cruzi DHFR, the three-dimensional structure of this protein in complex with various ligands is being studied. Here, the crystal structures of T. cruzi DHFR-TS with three different compositions of the DHFR domain are reported: the folate-free state, the complex with the lipophilic antifolate trimetrexate (TMQ) and the complex with the classical antifolate methotrexate (MTX). These structures reveal that the enzyme is a homodimer with substantial interactions between the two TS domains of neighboring subunits. In contrast to the enzymes from Cryptosporidium hominis and Plasmodium falciparum, the DHFR and TS active sites of T. cruzi lie on the same side of the monomer. As in other parasitic DHFR-TS proteins, the N-terminal extension of the T. cruzi enzyme is involved in extensive interactions between the two domains. The DHFR active site of the T. cruzi enzyme shows subtle differences compared with its human counterpart. These differences may be exploited for the development of antifolate-based therapeutic agents for the treatment of T. cruzi infection.
Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate.,Senkovich O, Schormann N, Chattopadhyay D Acta Crystallogr D Biol Crystallogr. 2009 Jul;65(Pt 7):704-16. Epub 2009, Jun 20. PMID:19564691[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Senkovich O, Schormann N, Chattopadhyay D. Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate. Acta Crystallogr D Biol Crystallogr. 2009 Jul;65(Pt 7):704-16. Epub 2009, Jun 20. PMID:19564691 doi:10.1107/S090744490901230X
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