7WPL

Methionyl-tRNA synthetase from Staphylococcus aureus complexed with ATP

Summary for 7WPL

• Entry DOI: 10.2210/pdb7wpl/pdb
• Descriptor: Methionine--tRNA ligase, ADENOSINE-5'-TRIPHOSPHATE, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: ligase
• Biological source: Staphylococcus aureus subsp. aureus COL (Staphylococcus aureus COL)
• Total number of polymer chains: 1
• Total formula weight: 61735.29

Authors

Yi, J.,Cai, Z.,Qiu, H.,Lu, F.,Chen, B.,Luo, Z.,Gu, Q.,Xu, J.,Zhou, H. (deposition date: 2022-01-24, release date: 2022-04-27, Last modification date: 2023-11-29)

Primary citation

Yi, J.,Cai, Z.,Qiu, H.,Lu, F.,Luo, Z.,Chen, B.,Gu, Q.,Xu, J.,Zhou, H.
Fragment screening and structural analyses highlight the ATP-assisted ligand binding for inhibitor discovery against type 1 methionyl-tRNA synthetase.
Nucleic Acids Res., 50:4755-4768, 2022

PubMed Abstract: Methionyl-tRNA synthetase (MetRS) charges tRNAMet with l-methionine (L-Met) to decode the ATG codon for protein translation, making it indispensable for all cellular lives. Many gram-positive bacteria use a type 1 MetRS (MetRS1), which is considered a promising antimicrobial drug target due to its low sequence identity with human cytosolic MetRS (HcMetRS, which belongs to MetRS2). Here, we report crystal structures of a representative MetRS1 from Staphylococcus aureus (SaMetRS) in its apo and substrate-binding forms. The connecting peptide (CP) domain of SaMetRS differs from HcMetRS in structural organization and dynamic movement. We screened 1049 chemical fragments against SaMetRS preincubated with or without substrate ATP, and ten hits were identified. Four cocrystal structures revealed that the fragments bound to either the L-Met binding site or an auxiliary pocket near the tRNA CCA end binding site of SaMetRS. Interestingly, fragment binding was enhanced by ATP in most cases, suggesting a potential ATP-assisted ligand binding mechanism in MetRS1. Moreover, co-binding with ATP was also observed in our cocrystal structure of SaMetRS with a class of newly reported inhibitors that simultaneously occupied the auxiliary pocket, tRNA site and L-Met site. Our findings will inspire the development of new MetRS1 inhibitors for fighting microbial infections.

PubMed: 35474479
DOI: 10.1093/nar/gkac285

Experimental method

X-RAY DIFFRACTION (2.5 Å)