3rg9: Difference between revisions

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==Trypanosoma brucei dihydrofolate reductase (TbDHFR) in complex with WR99210==
==Trypanosoma brucei dihydrofolate reductase (TbDHFR) in complex with WR99210==
<StructureSection load='3rg9' size='340' side='right' caption='[[3rg9]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='3rg9' size='340' side='right'caption='[[3rg9]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3rg9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_brucei_rhodesiense Trypanosoma brucei rhodesiense]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RG9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RG9 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3rg9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_rhodesiense Trypanosoma brucei rhodesiense]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RG9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RG9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=WRA:6,6-DIMETHYL-1-[3-(2,4,5-TRICHLOROPHENOXY)PROPOXY]-1,6-DIHYDRO-1,3,5-TRIAZINE-2,4-DIAMINE'>WRA</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&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qfx|3qfx]], [[3qg2|3qg2]], [[3qg9|3qg9]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=WRA:6,6-DIMETHYL-1-[3-(2,4,5-TRICHLOROPHENOXY)PROPOXY]-1,6-DIHYDRO-1,3,5-TRIAZINE-2,4-DIAMINE'>WRA</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHFR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31286 Trypanosoma brucei rhodesiense])</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=3rg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rg9 OCA], [https://pdbe.org/3rg9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rg9 RCSB], [https://www.ebi.ac.uk/pdbsum/3rg9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rg9 ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </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=3rg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rg9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3rg9 RCSB], [http://www.ebi.ac.uk/pdbsum/3rg9 PDBsum]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/DRTS_TRYBB DRTS_TRYBB] 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).
Dihydrofolate reductase (DHFR) is a potential drug target for Trypanosoma brucei, a human parasite, which is the causative agent for African sleeping sickness. No drug is available against this target, since none of the classical antifolates such as pyrimethamine (PYR), cycloguanil, or trimethoprim are effective as selective inhibitors of T. brucei DHFR (TbDHFR). In order to design effective drugs that target TbDHFR, co-crystal structures with bound antifolates were studied. On comparison with malarial Plasmodium falciparum DHFR (PfDHFR), the co-crystal structures of wild-type TbDHFR reveal greater structural similarities to a mutant PfDHFR causing antifolate resistance than the wild-type enzyme. TbDHFR imposes steric hindrance for rigid inhibitors like PYR around Thr86, which is equivalent to Ser108Asn of the malarial enzymes. In addition, a missing residue on TbDHFR active-site loop together with the presence of Ile51 widens its active site even further than the structural effect of Asn51Ile, which is observed in PfDHFR structures. The structural similarities are paralleled by the similarly poor affinities of the trypanosomal enzyme for rigid inhibitors. Mutations of TbDHFR at Thr86 resulted in 10-fold enhancement or 7-fold reduction in the rigid inhibitors affinities for Thr86Ser or Thr86Asn, respectively. The co-crystal structure of TbDHFR with a flexible antifolate WR99210 suggests that its greater affinity result from its ability to avoid such Thr86 clash and occupy the widened binding space similarly to what is observed in the PfDHFR structures. Natural resistance to antifolates of TbDHFR can therefore be explained, and potential antifolate chemotherapy of trypanosomiasis should be possible taking this into account.
 
Trypanosomal Dihydrofolate Reductase Reveals Natural Antifolate Resistance.,Vanichtanankul J, Taweechai S, Yuvaniyama J, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Yuthavong Y ACS Chem Biol. 2011 Jun 16. PMID:21650210<ref>PMID:21650210</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>


==See Also==
==See Also==
*[[Dihydrofolate reductase|Dihydrofolate reductase]]
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Dihydrofolate reductase]]
[[Category: Large Structures]]
[[Category: Trypanosoma brucei rhodesiense]]
[[Category: Trypanosoma brucei rhodesiense]]
[[Category: Vanichtanankul, J]]
[[Category: Vanichtanankul J]]
[[Category: Yuthavong, Y]]
[[Category: Yuthavong Y]]
[[Category: Yuvaniyama, J]]
[[Category: Yuvaniyama J]]
[[Category: Oxidoreductase]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
[[Category: Trypanosoma brucei]]
[[Category: Wr99210]]

Latest revision as of 11:35, 20 March 2024

Trypanosoma brucei dihydrofolate reductase (TbDHFR) in complex with WR99210Trypanosoma brucei dihydrofolate reductase (TbDHFR) in complex with WR99210

Structural highlights

3rg9 is a 2 chain structure with sequence from Trypanosoma brucei rhodesiense. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DRTS_TRYBB 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).

See Also

3rg9, resolution 2.00Å

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