View source for 5jdc


==Trypanosoma brucei PTR1 in complex with inhibitor NP-13 (Hesperetin)==
<StructureSection load='5jdc' size='340' side='right'caption='[[5jdc]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5jdc]] 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=5JDC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JDC 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]] 1.78&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6JP:(2S)-5,7-DIHYDROXY-2-(3-HYDROXY-4-METHOXYPHENYL)-2,3-DIHYDRO-4H-1-BENZOPYRAN-4-ONE'>6JP</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CSX:S-OXY+CYSTEINE'>CSX</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=OCS:CYSTEINESULFONIC+ACID'>OCS</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=5jdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jdc OCA], [https://pdbe.org/5jdc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jdc RCSB], [https://www.ebi.ac.uk/pdbsum/5jdc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jdc ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/O76290_TRYBB O76290_TRYBB] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 muM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 muM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs.,Borsari C, Luciani R, Pozzi C, Poehner I, Henrich S, Trande M, Cordeiro-da-Silva A, Santarem N, Baptista C, Tait A, Di Pisa F, Dello Iacono L, Landi G, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Gribbon P, Kohler M, Keminer O, Behrens B, Costantino L, Tejera Nevado P, Bifeld E, Eick J, Clos J, Torrado J, Jimenez-Anton MD, Corral MJ, Alunda JM, Pellati F, Wade RC, Ferrari S, Mangani S, Costi MP J Med Chem. 2016 Aug 25;59(16):7598-616. doi: 10.1021/acs.jmedchem.6b00698. Epub , 2016 Aug 5. PMID:27411733<ref>PMID:27411733</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5jdc" style="background-color:#fffaf0;"></div>

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