5XMP

Plasmodium vivax SHMT(C346A) bound with PLP-glycine and MF057

5XMP の概要

• エントリーDOI: 10.2210/pdb5xmp/pdb
• 分子名称: Serine hydroxymethyltransferase, N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE], 4-[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]-~{N}-methyl-~{N}-[2,2,2-tris(fluoranyl)ethyl]benzenesulfonamide, ... (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
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 150481.55

構造登録者

Chitnumsub, P.,Jaruwat, A.,Leartsakulpanich, U.,Schwertz, G.,Diederich, F. (登録日: 2017-05-16, 公開日: 2017-11-29, 最終更新日: 2023-11-22)

主引用文献

Schwertz, G.,Frei, M.S.,Witschel, M.C.,Rottmann, M.,Leartsakulpanich, U.,Chitnumsub, P.,Jaruwat, A.,Ittarat, W.,Schafer, A.,Aponte, R.A.,Trapp, N.,Mark, K.,Chaiyen, P.,Diederich, F.
Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs
Chemistry, 23:14345-14357, 2017

PubMed Abstract: Malaria remains a major threat to mankind due to the perpetual emergence of resistance against marketed drugs. Twenty-one pyrazolopyran-based inhibitors bearing terminal biphenyl, aryl sulfonamide, or aryl sulfone motifs were synthesized and tested towards serine hydroxymethyltransferase (SHMT), a key enzyme of the folate cycle. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target, as well as PfNF54 strains in cell-based assays in the low nanomolar range (18-56 nm). Seven co-crystal structures with P. vivax (Pv) SHMT were solved at 2.2-2.6 Å resolution. We observed an unprecedented influence of the torsion angle of ortho-substituted biphenyl moieties on cell-based efficacy. The peculiar lipophilic character of the sulfonyl moiety was highlighted in the complexes with aryl sulfonamide analogues, which bind in their preferred staggered orientation. The results are discussed within the context of conformational preferences in the ligands.

PubMed: 28967982
DOI: 10.1002/chem.201703244

実験手法

X-RAY DIFFRACTION (2.4 Å)