5GVM

Plasmodium vivax SHMT bound with PLP-glycine and GS557

5GVM の概要

• エントリーDOI: 10.2210/pdb5gvm/pdb
• 関連するPDBエントリー: 5GMK 5GML 5GMN 5GMP
• 分子名称: Serine hydroxymethyltransferase, putative, N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE], 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, ... (5 entities in total)
• 機能のキーワード: alpha and beta protein, methyltransferase activity, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Plasmodium vivax (strain Salvador I)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 150226.46

構造登録者

Chitnumsub, P.,Jaruwat, A.,Leartsakulpanich, U.,Schwertz, G. (登録日: 2016-09-06, 公開日: 2017-07-12, 最終更新日: 2023-11-08)

主引用文献

Schwertz, G.,Witschel, M.C.,Rottmann, M.,Bonnert, R.,Leartsakulpanich, U.,Chitnumsub, P.,Jaruwat, A.,Ittarat, W.,Schafer, A.,Aponte, R.A.,Charman, S.A.,White, K.L.,Kundu, A.,Sadhukhan, S.,Lloyd, M.,Freiberg, G.M.,Srikumaran, M.,Siggel, M.,Zwyssig, A.,Chaiyen, P.,Diederich, F.
Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
J. Med. Chem., 60:4840-4860, 2017

PubMed Abstract: 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 (t > 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 Å 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.

PubMed: 28537728
DOI: 10.1021/acs.jmedchem.7b00008

実験手法

X-RAY DIFFRACTION (2.24 Å)