View source for 2yhu


==Trypanosoma brucei PTR1 in complex with inhibitor WHF30==
<StructureSection load='2yhu' size='340' side='right'caption='[[2yhu]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2yhu]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YHU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YHU 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]] 2.01&#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=CSX:S-OXY+CYSTEINE'>CSX</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=WHF:3-(5-AMINO-1,3,4-THIADIAZOL-2-YL)-1-THIOPHEN-2-YLPROPAN-1-ONE'>WHF</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=2yhu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yhu OCA], [https://pdbe.org/2yhu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2yhu RCSB], [https://www.ebi.ac.uk/pdbsum/2yhu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2yhu ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/O76290_TRYBB O76290_TRYBB] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 muM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained.

Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery.,Linciano P, Dawson A, Pohner I, Costa DM, Sa MS, Cordeiro-da-Silva A, Luciani R, Gul S, Witt G, Ellinger B, Kuzikov M, Gribbon P, Reinshagen J, Wolf M, Behrens B, Hannaert V, Michels PAM, Nerini E, Pozzi C, di Pisa F, Landi G, Santarem N, Ferrari S, Saxena P, Lazzari S, Cannazza G, Freitas-Junior LH, Moraes CB, Pascoalino BS, Alcantara LM, Bertolacini CP, Fontana V, Wittig U, Muller W, Wade RC, Hunter WN, Mangani S, Costantino L, Costi MP ACS Omega. 2017 Sep 30;2(9):5666-5683. doi: 10.1021/acsomega.7b00473. Epub 2017, Sep 11. PMID:28983525<ref>PMID:28983525</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2yhu" style="background-color:#fffaf0;"></div>

==See Also==
*[[Pteridine reductase|Pteridine reductase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei]]
[[Category: Costi MP]]
[[Category: Dawson A]]
[[Category: Hunter WN]]
[[Category: Nerini E]]