7X5N

Crystal structure of E. faecium SHMT in complex with (+)-SHIN-1 and PLP-Ser

7X5N の概要

• エントリーDOI: 10.2210/pdb7x5n/pdb
• 関連するPDBエントリー: 7V3D
• 分子名称: Serine hydroxymethyltransferase, (4R)-6-azanyl-4-[3-(hydroxymethyl)-5-phenyl-phenyl]-3-methyl-4-propan-2-yl-1H-pyrano[2,3-c]pyrazole-5-carbonitrile, [3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YLMETHYL]-SERINE, ... (4 entities in total)
• 機能のキーワード: e. faecium, serine hydroxymethyltransferase, 1c metabolism, transferase
• 由来する生物種: Enterococcus faecium
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 91483.49

構造登録者

Hasegawa, K.,Hayashi, H. (登録日: 2022-03-05, 公開日: 2022-07-06, 最終更新日: 2024-05-29)

主引用文献

Makino, Y.,Oe, C.,Iwama, K.,Suzuki, S.,Nishiyama, A.,Hasegawa, K.,Okuda, H.,Hirata, K.,Ueno, M.,Kawaji, K.,Sasano, M.,Usui, E.,Hosaka, T.,Yabuki, Y.,Shirouzu, M.,Katsumi, M.,Murayama, K.,Hayashi, H.,Kodama, E.N.
Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors.
Commun Biol, 5:619-619, 2022

PubMed Abstract: Serine hydroxymethyltransferase (SHMT) produces 5,10-methylenetetrahydrofolate (CH-THF) from tetrahydrofolate with serine to glycine conversion. SHMT is a potential drug target in parasites, viruses and cancer. (+)-SHIN-1 was developed as a human SHMT inhibitor for cancer therapy. However, the potential of SHMT as an antibacterial target is unknown. Here, we show that (+)-SHIN-1 bacteriostatically inhibits the growth of Enterococcus faecium at a 50% effective concentration of 10 M and synergistically enhances the antibacterial activities of several nucleoside analogues. Our results, including crystal structure analysis, indicate that (+)-SHIN-1 binds tightly to E. faecium SHMT (efmSHMT). Two variable loops in SHMT are crucial for inhibitor binding, and serine binding to efmSHMT enhances the affinity of (+)-SHIN-1 by stabilising the loop structure of efmSHMT. The findings highlight the potency of SHMT as an antibacterial target and the possibility of developing SHMT inhibitors for treating bacterial, viral and parasitic infections and cancer.

PubMed: 35739195
DOI: 10.1038/s42003-022-03555-x

実験手法

X-RAY DIFFRACTION (1.9 Å)