4eil - Revision history

OCA at 15:02, 14 March 2024

2024-03-14T15:02:28Z

← Older revision		Revision as of 15:02, 14 March 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4eil]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EIL FirstGlance]. <br>		<table><tr><td colspan='2'>[[4eil]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EIL FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</scene>, <scene name='pdbligand=FOL:FOLIC+ACID'>FOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</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]] 2.1971Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</scene>, <scene name='pdbligand=FOL:FOLIC+ACID'>FOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</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=4eil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eil OCA], [https://pdbe.org/4eil PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eil RCSB], [https://www.ebi.ac.uk/pdbsum/4eil PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eil ProSAT]</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=4eil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eil OCA], [https://pdbe.org/4eil PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eil RCSB], [https://www.ebi.ac.uk/pdbsum/4eil PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eil ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[https://www.uniprot.org/uniprot/DRTS_TOXGO DRTS_TOXGO]] 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 (By similarity).		[https://www.uniprot.org/uniprot/DRTS_TOXGO DRTS_TOXGO] 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 (By similarity).
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	Most species, such as humans, have monofunctional forms of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) that are key folate metabolism enzymes making critical folate components required for DNA synthesis. In contrast, several parasitic protozoa, including Toxoplasma gondii, contain a unique bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) having the catalytic activities contained on a single polypeptide chain. The prevalence of T. gondii infection across the world, especially for those immunocompromised, underscores the need to understand TS-DHFR enzyme function and to find new avenues to exploit for the design of novel antiparasitic drugs. As a first step, we have solved the first three-dimensional structures of T. gondii TS-DHFR at 3.7 A and of a loop truncated TS-DHFR, removing several flexible surface loops in the DHFR domain, improving resolution to 2.2 A. Distinct structural features of the TS-DHFR homodimer include a junctional region containing a kinked crossover helix between the DHFR domains of the two adjacent monomers, a long linker connecting the TS and DHFR domains, and a DHFR domain that is positively charged. The roles of these unique structural features were probed by site-directed mutagenesis coupled with pre-steady state and steady state kinetics. Mutational analysis of the crossover helix region combined with kinetic characterization established the importance of this region not only in DHFR catalysis but also in modulating the distal TS activity, suggesting a role for TS-DHFR interdomain interactions. Additional kinetic studies revealed that substrate channeling occurs in which dihydrofolate is directly transferred from the TS to DHFR active site without entering bulk solution. The crystal structure suggests that the positively charged DHFR domain governs this electrostatically mediated movement of dihydrofolate, preventing release from the enzyme. Taken together, these structural and kinetic studies reveal unique, functional regions on the T. gondii TS-DHFR enzyme that may targeted for inhibition, thus paving the way for designing species specific inhibitors.

	First Three-Dimensional Structure of Toxoplasma gondii thymidylate synthase-dihydrofolate reductase: Insights for Catalysis, Interdomain Interactions, and Substrate Channeling.,Sharma H, Landau MJ, Vargo MA, Spasov KA, Anderson KS Biochemistry. 2013 Sep 20. PMID:24053355<ref>PMID:24053355</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4eil" style="background-color:#fffaf0;"></div>~~

	==See Also==		==See Also==
	*[[Dihydrofolate reductase 3D structures\|Dihydrofolate reductase 3D structures]]		*[[Dihydrofolate reductase 3D structures\|Dihydrofolate reductase 3D structures]]
	~~== References ==~~
	~~<references/>~~
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 07:12, 28 September 2022

2022-09-28T07:12:55Z

← Older revision		Revision as of 07:12, 28 September 2022
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	<StructureSection load='4eil' size='340' side='right'caption='[[4eil]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='4eil' size='340' side='right'caption='[[4eil]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4eil]] is a 8 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Toxgo Toxgo~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4EIL FirstGlance]. <br>		<table><tr><td colspan='2'>[[4eil]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EIL FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</scene>, <scene name='pdbligand=FOL:FOLIC+ACID'>FOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene>~~</td></tr>~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</scene>, <scene name='pdbligand=FOL:FOLIC+ACID'>FOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr>
	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DRTS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5811 TOXGO])~~</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=4eil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eil OCA], [https://pdbe.org/4eil PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eil RCSB], [https://www.ebi.ac.uk/pdbsum/4eil PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eil 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=4eil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eil OCA], [~~http~~://pdbe.org/4eil PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4eil RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4eil PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4eil ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[~~http~~://www.uniprot.org/uniprot/DRTS_TOXGO DRTS_TOXGO]] 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 (By similarity).		[[https://www.uniprot.org/uniprot/DRTS_TOXGO DRTS_TOXGO]] 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 (By similarity).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: ~~Toxgo~~]]		[[Category: Toxoplasma gondii]]
	[[Category: Sharma, H]]		[[Category: Sharma H]]
	~~[[Category: Bifunctional]]~~
	~~[[Category: Oxidoreductase]]~~
	~~[[Category: Transferase~~]]

OCA at 11:51, 17 July 2019

2019-07-17T11:51:30Z

← Older revision		Revision as of 11:51, 17 July 2019
Line 1:		Line 1:

	==Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR==		==Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR==
	<StructureSection load='4eil' size='340' side='right' caption='[[4eil]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='4eil' size='340' side='right'caption='[[4eil]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4eil]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Toxgo Toxgo]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EIL FirstGlance]. <br>		<table><tr><td colspan='2'>[[4eil]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Toxgo Toxgo]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EIL FirstGlance]. <br>
Line 21:		Line 21:

	==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: Large Structures]]
	[[Category: Toxgo]]		[[Category: Toxgo]]
	[[Category: Sharma, H]]		[[Category: Sharma, H]]

OCA at 19:33, 4 August 2016

2016-08-04T19:33:08Z

← Older revision		Revision as of 19:33, 4 August 2016
Line 1:		Line 1:

	==Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR==		==Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR==
	<StructureSection load='4eil' size='340' side='right' caption='[[4eil]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='4eil' size='340' side='right' caption='[[4eil]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4eil]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Toxoplasma_gondii Toxoplasma gondii~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EIL FirstGlance]. <br>		<table><tr><td colspan='2'>[[4eil]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Toxgo Toxgo]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EIL FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</scene>, <scene name='pdbligand=FOL:FOLIC+ACID'>FOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</scene>, <scene name='pdbligand=FOL:FOLIC+ACID'>FOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DRTS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5811 ~~Toxoplasma gondii~~])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DRTS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5811 TOXGO])</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=4eil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eil OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eil RCSB], [http://www.ebi.ac.uk/pdbsum/4eil 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=4eil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eil OCA], [http://pdbe.org/4eil PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4eil RCSB], [http://www.ebi.ac.uk/pdbsum/4eil PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4eil ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 17:		Line 18:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 4eil" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 24:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Toxoplasma gondii~~]]		[[Category: Toxgo]]
	[[Category: Sharma, H]]		[[Category: Sharma, H]]
	[[Category: Bifunctional]]		[[Category: Bifunctional]]
	[[Category: Oxidoreductase]]		[[Category: Oxidoreductase]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 18:49, 24 December 2014

2014-12-24T18:49:19Z

← Older revision		Revision as of 18:49, 24 December 2014
Line 7:		Line 7:
	<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=4eil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eil OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eil RCSB], [http://www.ebi.ac.uk/pdbsum/4eil 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=4eil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eil OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eil RCSB], [http://www.ebi.ac.uk/pdbsum/4eil PDBsum]</span></td></tr>
	</table>		</table>
			== Function ==
			[[http://www.uniprot.org/uniprot/DRTS_TOXGO DRTS_TOXGO]] 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 (By similarity).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 11:19, 21 December 2014

2014-12-21T11:19:34Z

← Older revision		Revision as of 11:19, 21 December 2014
Line 1:		Line 1:
	~~{{STRUCTURE_4eil~~\| ~~PDB~~=4eil \| ~~SCENE~~= }}		==Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR==
	===~~Crystal Structure~~ of the loop truncated ~~Toxoplasma~~ gondii TS-DHFR~~===~~		<StructureSection load='4eil' size='340' side='right' caption='[[4eil]], [[Resolution\|resolution]] 2.20Å' scene=''>
	~~{{ABSTRACT_PUBMED_24053355}}~~		== Structural highlights ==
			<table><tr><td colspan='2'>[[4eil]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EIL FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</scene>, <scene name='pdbligand=FOL:FOLIC+ACID'>FOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DRTS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5811 Toxoplasma gondii])</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=4eil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eil OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eil RCSB], [http://www.ebi.ac.uk/pdbsum/4eil PDBsum]</span></td></tr>
			</table>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Most species, such as humans, have monofunctional forms of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) that are key folate metabolism enzymes making critical folate components required for DNA synthesis. In contrast, several parasitic protozoa, including Toxoplasma gondii, contain a unique bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) having the catalytic activities contained on a single polypeptide chain. The prevalence of T. gondii infection across the world, especially for those immunocompromised, underscores the need to understand TS-DHFR enzyme function and to find new avenues to exploit for the design of novel antiparasitic drugs. As a first step, we have solved the first three-dimensional structures of T. gondii TS-DHFR at 3.7 A and of a loop truncated TS-DHFR, removing several flexible surface loops in the DHFR domain, improving resolution to 2.2 A. Distinct structural features of the TS-DHFR homodimer include a junctional region containing a kinked crossover helix between the DHFR domains of the two adjacent monomers, a long linker connecting the TS and DHFR domains, and a DHFR domain that is positively charged. The roles of these unique structural features were probed by site-directed mutagenesis coupled with pre-steady state and steady state kinetics. Mutational analysis of the crossover helix region combined with kinetic characterization established the importance of this region not only in DHFR catalysis but also in modulating the distal TS activity, suggesting a role for TS-DHFR interdomain interactions. Additional kinetic studies revealed that substrate channeling occurs in which dihydrofolate is directly transferred from the TS to DHFR active site without entering bulk solution. The crystal structure suggests that the positively charged DHFR domain governs this electrostatically mediated movement of dihydrofolate, preventing release from the enzyme. Taken together, these structural and kinetic studies reveal unique, functional regions on the T. gondii TS-DHFR enzyme that may targeted for inhibition, thus paving the way for designing species specific inhibitors.

	~~==Function==~~		First Three-Dimensional Structure of Toxoplasma gondii thymidylate synthase-dihydrofolate reductase: Insights for Catalysis, Interdomain Interactions, and Substrate Channeling.,Sharma H, Landau MJ, Vargo MA, Spasov KA, Anderson KS Biochemistry. 2013 Sep 20. PMID:24053355<ref>PMID:24053355</ref>
	~~[[http~~:~~//www.uniprot.org/uniprot/DRTS_TOXGO DRTS_TOXGO]] 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 (By similarity)~~.

	~~==About this Structure==~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~[[4eil]] is~~ a ~~8 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Toxoplasma_gondii Toxoplasma gondii]~~. ~~Full crystallographic information is available from [http:/~~/~~oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA].~~		</div>

	==~~Reference~~==		==See Also==
	~~<ref group~~=~~"xtra">PMID:024053355</ref>~~<references ~~group="xtra"~~/><~~references~~/>		*[[Dihydrofolate reductase\|Dihydrofolate reductase]]
			== References ==
			<references/>
			__TOC__
			</StructureSection>
	[[Category: Toxoplasma gondii]]		[[Category: Toxoplasma gondii]]
	[[Category: Sharma, H.]]		[[Category: Sharma, H]]
	[[Category: Bifunctional]]		[[Category: Bifunctional]]
	[[Category: Oxidoreductase]]		[[Category: Oxidoreductase]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 06:20, 10 October 2013

2013-10-10T06:20:33Z

← Older revision		Revision as of 06:20, 10 October 2013
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	~~'''Unreleased structure'''~~		{{STRUCTURE_4eil\| PDB=4eil \| SCENE= }}
			===Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR===
			{{ABSTRACT_PUBMED_24053355}}

	~~The entry 4eil is ON HOLD until Paper Publication~~		==Function==
			[[http://www.uniprot.org/uniprot/DRTS_TOXGO DRTS_TOXGO]] 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 (By similarity).

	~~Authors~~: ~~Sharma, H~~.		==About this Structure==
			[[4eil]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EIL OCA].

	~~Description~~: ~~Crystal Structure of the loop truncated~~ Toxoplasma gondii ~~TS-DHFR~~		==Reference==
			<ref group="xtra">PMID:024053355</ref><references group="xtra"/><references/>
			[[Category: Toxoplasma gondii]]
			[[Category: Sharma, H.]]
			[[Category: Bifunctional]]
			[[Category: Oxidoreductase]]
			[[Category: Transferase]]

OCA at 06:34, 2 October 2013

2013-10-02T06:34:18Z

← Older revision		Revision as of 06:34, 2 October 2013
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4eil is ON HOLD until ~~Oct 01 2014~~		The entry 4eil is ON HOLD until Paper Publication

	Authors: Sharma, H.		Authors: Sharma, H.

	Description: Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR		Description: Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR

OCA at 09:32, 4 September 2013

2013-09-04T09:32:35Z

← Older revision		Revision as of 09:32, 4 September 2013
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4eil is ON HOLD until ~~Sep~~ 01 2014		The entry 4eil is ON HOLD until Oct 01 2014

	Authors: Sharma, H.		Authors: Sharma, H.

	Description: Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR		Description: Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR

OCA at 19:45, 7 August 2013

2013-08-07T19:45:10Z

← Older revision		Revision as of 19:45, 7 August 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4eil is ON HOLD until ~~Paper Publication~~		The entry 4eil is ON HOLD until Sep 01 2014

	Authors: Sharma, H.		Authors: Sharma, H.

	Description: Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR		Description: Crystal Structure of the loop truncated Toxoplasma gondii TS-DHFR