5gvm: Difference between revisions
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==Plasmodium vivax SHMT bound with PLP-glycine and GS557== | |||
<StructureSection load='5gvm' size='340' side='right' caption='[[5gvm]], [[Resolution|resolution]] 2.24Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5gvm]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5GVM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5GVM FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=G57:2-[3-[3-[(4~{S})-6-azanyl-5-cyano-3-methyl-4-propan-2-yl-2~{H}-pyrano[2,3-c]pyrazol-4-yl]-5-(trifluoromethyl)phenyl]phenyl]ethanoic+acid'>G57</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">[[5gmp|5gmp]], [[5gmn|5gmn]], [[5gml|5gml]], [[5gmk|5gmk]]</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=5gvm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gvm OCA], [http://pdbe.org/5gvm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5gvm RCSB], [http://www.ebi.ac.uk/pdbsum/5gvm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5gvm ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 A resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel. | |||
Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures.,Schwertz G, Witschel MC, Rottmann M, Bonnert R, Leartsakulpanich U, Chitnumsub P, Jaruwat A, Ittarat W, Schafer A, Aponte RA, Charman SA, White KL, Kundu A, Sadhukhan S, Lloyd M, Freiberg GM, Srikumaran M, Siggel M, Zwyssig A, Chaiyen P, Diederich F J Med Chem. 2017 Jun 22;60(12):4840-4860. doi: 10.1021/acs.jmedchem.7b00008. Epub, 2017 Jun 13. PMID:28537728<ref>PMID:28537728</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5gvm" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Chitnumsub, P]] | |||
[[Category: Jaruwat, A]] | [[Category: Jaruwat, A]] | ||
[[Category: Leartsakulpanich, U]] | [[Category: Leartsakulpanich, U]] | ||
[[Category: Schwertz, G]] | [[Category: Schwertz, G]] | ||
[[Category: Alpha and beta protein]] | |||
[[Category: Methyltransferase activity]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||