7DB7

Crystal structure of Mycobacterium tuberculosis phenylalanyl-tRNA synthetase in complex with compound GDI05-001

Summary for 7DB7

• Entry DOI: 10.2210/pdb7db7/pdb
• Related: 7DAW
• Descriptor: Phenylalanine--tRNA ligase alpha subunit, Phenylalanine--tRNA ligase beta subunit, 1-[3-[2-(1H-indol-3-yl)ethylsulfamoyl]phenyl]-3-(1,3-thiazol-2-yl)urea, ... (5 entities in total)
• Functional Keywords: aminoacylation, trna-binding, aminoacyl-trna synthetase, atp-binding, ligase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 2
• Total formula weight: 129189.35

Authors

Xu, M.,Zhang, X.,Xu, L.,Chen, S. (deposition date: 2020-10-19, release date: 2021-01-13, Last modification date: 2023-11-29)

Primary citation

Wang, H.,Xu, M.,Engelhart, C.A.,Zhang, X.,Yan, B.,Pan, M.,Xu, Y.,Fan, S.,Liu, R.,Xu, L.,Hua, L.,Schnappinger, D.,Chen, S.
Re-discovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis .
J.Biol.Chem., 2021

PubMed Abstract: Mycobacteria tuberculosis (Mtb) remains the deadliest pathogenic bacteria worldwide. The search for new antibiotics to treat drug-sensitive as well as drug-resistant tuberculosis has become a priority. The essential enzyme phenylalanyl-tRNA synthetase (PheRS) is an antibacterial drug target because of the large differences between bacterial and human PheRS counterparts. In a high-throughput screening of 2148 bioactive compounds, PF-3845, which is a known inhibitor of human fatty acid amide hydrolase (FAAH), was identified inhibiting Mtb PheRS at ~0.73 ± 0.06 µM. The inhibition mechanism was studied with enzyme kinetics, protein structural modelling and crystallography, in comparison to a PheRS inhibitor of the noted phenyl-thiazolylurea-sulfonamide class. The 2.3-Å crystal structure of Mtb PheRS in complex with PF-3845 revealed its novel binding mode, in which a trifluoromethyl-pyridinylphenyl group occupies the Phe pocket while a piperidine-piperazine urea group binds into the ATP pocket through an interaction network enforced by a sulfate ion. It represents the first non-nucleoside bi-substrate competitive inhibitor of bacterial PheRS. PF-3845 inhibits the growth of Mtb H37Rv at ~24 µM, and the potency of PF-3845 increased against Mtb pheS-FDAS, suggesting on target activity in mycobacterial whole cells.  PF-3845 does not inhibit human cytoplasmic or mitochondrial PheRS in biochemical assay, which can be explained from the crystal structures. Further medicinal chemistry efforts focused on the piperidine-piperazine urea moiety may result in the identification of a selective antibacterial lead compound.

PubMed: 33397709
DOI: 10.1074/jbc.RA120.016477

Experimental method

X-RAY DIFFRACTION (2.71 Å)