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''' | ==Crystal structure of pteridine reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor and inhibitor== | ||
<StructureSection load='4cmi' size='340' side='right' caption='[[4cmi]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4cmi]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CMI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CMI FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=M4V:2-AMINO-6-(4-BROMOPHENYL)-5-PHENYL-3H-PYRROLO[2,3-D]PYRIMIDIN-4(7H)-ONE'>M4V</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSX:S-OXY+CYSTEINE'>CSX</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4cl8|4cl8]], [[4cld|4cld]], [[4cle|4cle]], [[4clh|4clh]], [[4clo|4clo]], [[4clr|4clr]], [[4clx|4clx]], [[4cm1|4cm1]], [[4cm3|4cm3]], [[4cm4|4cm4]], [[4cm5|4cm5]], [[4cm6|4cm6]], [[4cm7|4cm7]], [[4cm8|4cm8]], [[4cm9|4cm9]], [[4cma|4cma]], [[4cmb|4cmb]], [[4cmc|4cmc]], [[4cme|4cme]], [[4cmg|4cmg]], [[4cmj|4cmj]], [[4cmk|4cmk]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pteridine_reductase Pteridine reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.33 1.5.1.33] </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=4cmi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cmi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cmi RCSB], [http://www.ebi.ac.uk/pdbsum/4cmi PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The 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<ref>PMID:25007262</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
[[Category: | <references/> | ||
[[Category: Hunter, W | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Pteridine reductase]] | |||
[[Category: Barrack, K L]] | |||
[[Category: Hunter, W N]] | |||
[[Category: Oxidoreductase]] | |||
[[Category: Short-chain dehydrogenase/reductase]] | |||
Revision as of 19:52, 21 January 2015
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
Publication 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. References
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