View source for 7opj


==Trypanosoma brucei PTR1 (TbPTR1) in complex with pyrimethamine==
<StructureSection load='7opj' size='340' side='right'caption='[[7opj]], [[Resolution|resolution]] 1.34&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7opj]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei Trypanosoma brucei brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OPJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OPJ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.34&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CP6:5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE'>CP6</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=7opj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7opj OCA], [https://pdbe.org/7opj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7opj RCSB], [https://www.ebi.ac.uk/pdbsum/7opj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7opj ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/O76290_TRYBB O76290_TRYBB] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine-nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy.

Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase.,Tassone G, Landi G, Linciano P, Francesconi V, Tonelli M, Tagliazucchi L, Costi MP, Mangani S, Pozzi C Pharmaceuticals (Basel). 2021 Jun 30;14(7). pii: ph14070636. doi:, 10.3390/ph14070636. PMID:34209148<ref>PMID:34209148</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7opj" style="background-color:#fffaf0;"></div>

==See Also==
*[[Pteridine reductase|Pteridine reductase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei brucei]]
[[Category: Landi G]]
[[Category: Mangani S]]
[[Category: Pozzi C]]
[[Category: Tassone G]]