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5t0l

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Current revision

Crystal structure of Toxoplasma gondii TS-DHFR complexed with NADPH, dUMP, PDDF and 5-(4-(3,4-dichlorophenyl)piperazin-1-yl)pyrimidine-2,4-diamine (TRC-15)

Structural highlights

5t0l is a 2 chain structure with sequence from Toxoplasma gondii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.13Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).

Publication Abstract from PubMed

Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between Toxoplasma gondii and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC50 of 9 nM and 89-fold selectivity in favor of Toxoplasma gondii DHFR, as well as crystallographic data to substantiate in silico methodology. Overall, 50% of synthesized in silico designs met hit threshold criteria of IC50 < 10 muM and >2-fold selectivity favoring Toxoplasma gondii, further demonstrating the efficiency of our structure-based drug design approach.

Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design.,Welsch ME, Zhou J, Gao Y, Yan Y, Porter G, Agnihotri G, Li Y, Lu H, Chen Z, Thomas SB ACS Med Chem Lett. 2016 Sep 17;7(12):1124-1129. eCollection 2016 Dec 8. PMID:27994750^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Welsch ME, Zhou J, Gao Y, Yan Y, Porter G, Agnihotri G, Li Y, Lu H, Chen Z, Thomas SB. Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design. ACS Med Chem Lett. 2016 Sep 17;7(12):1124-1129. eCollection 2016 Dec 8. PMID:27994750 doi:http://dx.doi.org/10.1021/acsmedchemlett.6b00328

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5t0l"

@@ Line 3: / Line 3: @@
 <StructureSection load='5t0l' size='340' side='right'caption='[[5t0l]], [[Resolution|resolution]] 3.13&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5t0l]] is a 2 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=5T0L OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5T0L FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5t0l]] is a 2 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=5T0L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T0L FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=73X:5-[4-(3,4-DICHLOROPHENYL)PIPERAZIN-1-YL]PYRIMIDINE-2,4-DIAMINE'>73X</scene>, <scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</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]] 3.13&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5t0l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t0l OCA], [http://pdbe.org/5t0l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t0l RCSB], [http://www.ebi.ac.uk/pdbsum/5t0l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t0l ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=73X:5-[4-(3,4-DICHLOROPHENYL)PIPERAZIN-1-YL]PYRIMIDINE-2,4-DIAMINE'>73X</scene>, <scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</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=5t0l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t0l OCA], [https://pdbe.org/5t0l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t0l RCSB], [https://www.ebi.ac.uk/pdbsum/5t0l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t0l ProSAT]</span></td></tr>
 </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).
+[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 ==
@@ Line 26: / Line 27: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Toxgo]]
-[[Category: Chen, Z]]
-[[Category: Li, Y]]
-[[Category: Lu, H]]
-[[Category: Thomas, S B]]
-[[Category: Dhfr]]
-[[Category: Inhibitor]]
-[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
 [[Category: Toxoplasma gondii]]
+[[Category: Chen Z]]
+[[Category: Li Y]]
+[[Category: Lu H]]
+[[Category: Thomas SB]]

5t0l

From Proteopedia

Current revision

Crystal structure of Toxoplasma gondii TS-DHFR complexed with NADPH, dUMP, PDDF and 5-(4-(3,4-dichlorophenyl)piperazin-1-yl)pyrimidine-2,4-diamine (TRC-15)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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