4tn4: Difference between revisions
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==Crystal structure of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran 33G: (4S)-6-amino-4-(5-cyano-3'-fluorobiphenyl-3-yl)-4-cyclobutyl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile== | ==Crystal structure of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran 33G: (4S)-6-amino-4-(5-cyano-3'-fluorobiphenyl-3-yl)-4-cyclobutyl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile== | ||
<StructureSection load='4tn4' size='340' side='right' caption='[[4tn4]], [[Resolution|resolution]] 2.20Å' scene=''> | <StructureSection load='4tn4' size='340' side='right' caption='[[4tn4]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=33G:(4S)-6-AMINO-4-(5-CYANO-3-FLUOROBIPHENYL-3-YL)-4-CYCLOBUTYL-3-METHYL-2,4-DIHYDROPYRANO[2,3-C]PYRAZOLE-5-CARBONITRILE'>33G</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PLG:N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE]'>PLG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=33G:(4S)-6-AMINO-4-(5-CYANO-3-FLUOROBIPHENYL-3-YL)-4-CYCLOBUTYL-3-METHYL-2,4-DIHYDROPYRANO[2,3-C]PYRAZOLE-5-CARBONITRILE'>33G</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PLG:N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE]'>PLG</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pff|4pff]], [[4pfn|4pfn]], [[4oyt|4oyt]], [[4o6z|4o6z]], [[4tmr|4tmr]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pff|4pff]], [[4pfn|4pfn]], [[4oyt|4oyt]], [[4o6z|4o6z]], [[4tmr|4tmr]]</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=4tn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tn4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4tn4 RCSB], [http://www.ebi.ac.uk/pdbsum/4tn4 PDBsum]</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=4tn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tn4 OCA], [http://pdbe.org/4tn4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tn4 RCSB], [http://www.ebi.ac.uk/pdbsum/4tn4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4tn4 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4tn4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Serine hydroxymethyltransferase|Serine hydroxymethyltransferase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 03:08, 26 January 2017
Crystal structure of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran 33G: (4S)-6-amino-4-(5-cyano-3'-fluorobiphenyl-3-yl)-4-cyclobutyl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrileCrystal structure of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran 33G: (4S)-6-amino-4-(5-cyano-3'-fluorobiphenyl-3-yl)-4-cyclobutyl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
Structural highlights
Publication Abstract from PubMedSeveral of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 A resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model. Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities.,Witschel MC, Rottmann M, Schwab A, Leartsakulpanich U, Chitnumsub P, Seet M, Tonazzi S, Schwertz G, Stelzer F, Mietzner T, McNamara C, Thater F, Freymond C, Jaruwat A, Pinthong C, Riangrungroj P, Oufir M, Hamburger M, Maser P, Sanz-Alonso LM, Charman S, Wittlin S, Yuthavong Y, Chaiyen P, Diederich F J Med Chem. 2015 Mar 18. PMID:25785478[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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