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==Crystal structure of pteridine reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor and inhibitor== | ==Crystal structure of pteridine reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor and inhibitor== | ||
<StructureSection load='4cmc' size='340' side='right' caption='[[4cmc]], [[Resolution|resolution]] 1.85Å' scene=''> | <StructureSection load='4cmc' size='340' side='right'caption='[[4cmc]], [[Resolution|resolution]] 1.85Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4cmc]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CMC OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4cmc]] 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=4CMC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CMC FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=VS8:N4-CYCLOHEXYL-5,6-DIPHENYL-7H-PYRROLO[2,3-D]PYRIMIDINE-2,4-DIAMINE'>VS8</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=4cmc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cmc OCA], [https://pdbe.org/4cmc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cmc RCSB], [https://www.ebi.ac.uk/pdbsum/4cmc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cmc ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/O76290_TRYBB O76290_TRYBB] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Trypanosoma brucei brucei]] | ||
[[Category: | [[Category: Barrack KL]] | ||
[[Category: | [[Category: Hunter WN]] | ||
Latest revision as of 15:12, 20 December 2023
Crystal structure of pteridine reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor and inhibitorCrystal structure of pteridine reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor and inhibitor
Structural highlights
FunctionPublication Abstract from PubMedThe treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp., has been identified as a candidate target, and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from Trypanosoma brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. Eight compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus, although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development. Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1.,Khalaf AI, Huggan JK, Suckling CJ, Gibson CL, Stewart K, Giordani F, Barrett MP, Wong PE, Barrack KL, Hunter WN J Med Chem. 2014 Aug 14;57(15):6479-94. doi: 10.1021/jm500483b. Epub 2014 Jul 29. PMID:25007262[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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