5YFZ

Plasmodium vivax SHMT bound with PLP-glycine and S-GS626

5YFZ の概要

• エントリーDOI: 10.2210/pdb5yfz/pdb
• 分子名称: Serine hydroxymethyltransferase, N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE], 2-[1-[3-[(4~{S})-6-azanyl-5-cyano-3-methyl-4-propan-2-yl-2~{H}-pyrano[2,3-c]pyrazol-4-yl]-5-fluoranyl-phenyl]piperidin-4-yl]ethanoic acid, ... (5 entities in total)
• 機能のキーワード: alpha and beta protein, transferase, methyltransferase activity, inhibitor, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Plasmodium vivax
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 150097.54

構造登録者

Chitnumsub, P.,Jaruwat, A.,Leartsakulpanich, U.,Schwertz, G.,Diederich, F. (登録日: 2017-09-22, 公開日: 2018-06-06, 最終更新日: 2023-11-22)

主引用文献

Schwertz, G.,Witschel, M.C.,Rottmann, M.,Leartsakulpanich, U.,Chitnumsub, P.,Jaruwat, A.,Amornwatcharapong, W.,Ittarat, W.,Schafer, A.,Aponte, R.A.,Trapp, N.,Chaiyen, P.,Diederich, F.
Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold
ChemMedChem, 13:931-943, 2018

PubMed Abstract: With the discovery that serine hydroxymethyltransferase (SHMT) is a druggable target for antimalarials, the aim of this study was to design novel inhibitors of this key enzyme in the folate biosynthesis cycle. Herein, 19 novel spirocyclic ligands based on either 2-indolinone or dihydroindene scaffolds and featuring a pyrazolopyran core are reported. Strong target affinities for Plasmodium falciparum (Pf) SHMT (14-76 nm) and cellular potencies in the low nanomolar range (165-334 nm) were measured together with interesting selectivity against human cytosolic SHMT1 (hSHMT1). Four co-crystal structures with Plasmodium vivax (Pv) SHMT solved at 2.2-2.4 Å resolution revealed the key role of the vinylogous cyanamide for anchoring ligands within the active site. The spirocyclic motif in the molecules enforces the pyrazolopyran core to adopt a substantially more curved conformation than that of previous non-spirocyclic analogues. Finally, solvation of the spirocyclic lactam ring of the receptor-bound ligands is discussed.

PubMed: 29655285
DOI: 10.1002/cmdc.201800053

実験手法

X-RAY DIFFRACTION (2.16 Å)