PDBsum entry 6ykt

Ligase

PDB id: 6ykt

Contents

Protein chain

844 a.a.

Ligands

OVN

EDO ×2

Metals

_MG

_ZN

Waters ×194

PDB id:

6ykt

Name:

Ligase

Title:

Neisseria gonorrhoeae leucyl-tRNA synthetase in complex with compound 11e

Structure:

Leucine--tRNA ligase. Chain: a. Fragment: leucyl-tRNA synthetase. Synonym: leucyl-tRNA synthetase,leurs. Engineered: yes. Mutation: yes

Source:

Neisseria gonorrhoeae. Organism_taxid: 485. Gene: leus, vt05_02036, whoo_00006, whoo_00455. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_variant: rosetta 2 (de3) plyss.

Resolution:

2.32Å R-factor: 0.186 R-free: 0.237

Authors:

L.Pang,S.V.Strelkov,S.D.Weeks

Key ref:

D.De Ruysscher et al. (2021). Synthesis and structure-activity studies of novel anhydrohexitol-based Leucyl-tRNA synthetase inhibitors. Eur J Med Chem, 211, 113021-113021. PubMed id: 33248851 DOI: 10.1016/j.ejmech.2020.113021

Date:

06-Apr-20 Release date: 02-Dec-20

Protein chain

Q5FAJ3  (SYL_NEIG1) -  Leucine--tRNA ligase from Neisseria gonorrhoeae (strain ATCC 700825 / FA 1090)

Seq: 876 a.a.

Struc: 844 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.6.1.1.4 - leucine--tRNA ligase.
• Reaction: tRNA(Leu) + L-leucine + ATP = L-leucyl-tRNA(Leu) + AMP + diphosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.ejmech.2020.113021

Eur J Med Chem 211:113021-113021 (2021)

PubMed id: 33248851

Synthesis and structure-activity studies of novel anhydrohexitol-based Leucyl-tRNA synthetase inhibitors.

D.De Ruysscher, L.Pang, S.M.G.Lenders, D.Cappoen, P.Cos, J.Rozenski, S.V.Strelkov, S.D.Weeks, A.Van Aerschot.

ABSTRACT

Leucyl-tRNA synthetase (LeuRS) is a clinically validated target for the development of antimicrobials. This enzyme catalyzes the formation of charged tRNA^Leu molecules, an essential substrate for protein translation. In the first step of catalysis LeuRS activates leucine using ATP, forming a leucyl-adenylate intermediate. Bi-substrate inhibitors that mimic this chemically labile phosphoanhydride-linked nucleoside have proven to be potent inhibitors of different members of the aminoacyl-tRNA synthetase family but, to date, they have demonstrated poor antibacterial activity. We synthesized a small series of 1,5-anhydrohexitol-based analogues coupled to a variety of triazoles and performed detailed structure-activity relationship studies with bacterial LeuRS. In an in vitro assay, K_i^app values in the nanomolar range were demonstrated. Inhibitory activity differences between the compounds revealed that the polarity and size of the triazole substituents affect binding. X-ray crystallographic studies of N. gonorrhoeae LeuRS in complex with all the inhibitors highlighted the crucial interactions defining their relative enzyme inhibitory activities. We further examined their in vitro antimicrobial properties by screening against several bacterial and yeast strains. While only weak antibacterial activity against M. tuberculosis was detected, the extensive structural data which were obtained could make these LeuRS inhibitors a suitable starting point towards further antibiotic development.