View source for 4tmr


==Crystal structure of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran 99S: methyl 5-{3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl}thiophene-2-carboxylate .==
<StructureSection load='4tmr' size='340' side='right'caption='[[4tmr]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4tmr]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_vivax_Sal-1 Plasmodium vivax Sal-1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TMR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TMR 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]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=99S:METHYL+5-{3-[(4S)-6-AMINO-5-CYANO-3-METHYL-4-(PROPAN-2-YL)-2,4-DIHYDROPYRANO[2,3-C]PYRAZOL-4-YL]-5-CYANOPHENYL}THIOPHENE-2-CARBOXYLATE'>99S</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4tmr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tmr OCA], [https://pdbe.org/4tmr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tmr RCSB], [https://www.ebi.ac.uk/pdbsum/4tmr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tmr ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A5K8L9_PLAVS A5K8L9_PLAVS] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Several 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<ref>PMID:25785478</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4tmr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Plasmodium vivax Sal-1]]
[[Category: Chitnumsub P]]
[[Category: Jaruwat A]]
[[Category: Leartsakulpanich U]]
[[Category: Witschel MC]]