7V3D

Complex structure of serine hydroxymethyltransferase from Enterococcus faecium and its inhibitor

Summary for 7V3D

• Entry DOI: 10.2210/pdb7v3d/pdb
• Descriptor: 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, PYRIDOXAL-5'-PHOSPHATE, ... (5 entities in total)
• Functional Keywords: inhibitor, antibacterial mechanism, complex, transferase
• Biological source: Enterococcus faecium (Streptococcus faecium)
• Total number of polymer chains: 2
• Total formula weight: 91376.21

Authors

Hayashi, H.,Murayama, K. (deposition date: 2021-08-10, release date: 2022-07-06, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.28 Å)