9J4G

Crystal structure of SHMT from E. faecium with (+)-SHIN-2

This is a non-PDB format compatible entry.

Summary for 9J4G

• Entry DOI: 10.2210/pdb9j4g/pdb
• Descriptor: Serine hydroxymethyltransferase, [3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YLMETHYL]-SERINE, (+)-SHIN-2, ... (4 entities in total)
• Functional Keywords: one carbon metabolism, folate binding, transferase
• Biological source: Enterococcus faecium
• Total number of polymer chains: 2
• Total formula weight: 91495.50

Authors

Hayashi, H.,Murayama, K. (deposition date: 2024-08-09, release date: 2024-10-09)

Primary citation

Hayashi, H.,Saijo, E.,Hirata, K.,Murakami, S.,Okuda, H.,Kodama, E.N.,Hasegawa, K.,Murayama, K.
SHIN-2 exerts potent activity against VanA-type vancomycin-resistant Enterococcus faecium in vitro by stabilizing the active site loop of serine hydroxymethyltransferase.
Arch.Biochem.Biophys., 761:110160-110160, 2024

PubMed Abstract: Novel classes of antibiotics are needed to improve the resilience of the healthcare system to antimicrobial resistance (AMR), including vancomycin resistance. vanA gene cluster is a cause of vancomycin resistance. This gene cluster is transferred and spreads vancomycin resistance from Enterococcus spp. to Staphylococcus aureus. Therefore, novel antibacterial agents are required to combat AMR, including vanA-type vancomycin resistance. Serine hydroxymethyltransferase (SHMT) is a key target of antibacterial agents. However, the specific binding mechanisms of SHMT inhibitors remain unclear. Detailed structural information will contribute to understanding these mechanisms. In this study, we found that (+)-SHIN-2, the first in vivo active inhibitor of human SHMT, is strongly bound to the Enterococcus faecium SHMT (efmSHMT). Comparison of the crystal structures of apo- and (+)-SHIN-2-boud efmSHMT revealed that (+)-SHIN-2 stabilized the active site loop of efmSHMT via hydrogen bonds, which are critical for efmSHMT inhibition. Additionally, (+)-SHIN-2 formed hydrogen bonds with serine, forming the Schiff's base with pyridoxal 5'-phosphate, which is a co-factor of SHMT. Furthermore, (+)-SHIN-2 exerted biostatic effects on vancomycin-susceptible and vanA-type vancomycin-resistant E. faecium in vitro, indicating that SHMT inhibitors do not induce cross-resistance to vanA-type vancomycin. Overall, these findings can aid in the design of novel SHMT inhibitors to combat AMR, including vancomycin resistance.

PubMed: 39313141
DOI: 10.1016/j.abb.2024.110160

Experimental method

X-RAY DIFFRACTION (1.95 Å)