PDBsum entry 4zt2

Ligase/ligase inhibitor

PDB id: 4zt2

Contents

Protein chains

517 a.a.

Ligands

DMS ×5

MET

GOL ×3

4RP

SO4 ×2

Waters ×325

PDB id:

4zt2

Name:

Ligase/ligase inhibitor

Title:

Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor n-(3,5-dichlorobenzyl)-n'-(1h-imidazo[4,5-b]pyridin-2-yl)propane-1,3- diamine (chem 1575)

Structure:

Methionyl-tRNA synthetase. Chain: a, b. Fragment: unp residues 237-773. Engineered: yes. Mutation: yes

Source:

Trypanosoma brucei brucei. Organism_taxid: 185431. Strain: 927/4 gutat10.1. Gene: tb10.70.6470. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.70Å R-factor: 0.196 R-free: 0.228

Authors:

C.-Y.Koh,W.G.J.Hol

Key ref:

Z.Zhang et al. (2016). 5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors. Acs Infect Dis, 2, 399-404. PubMed id: 27627628 DOI: 10.1021/acsinfecdis.6b00036

Date:

14-May-15 Release date: 04-May-16

Protein chains

Q38C91  (Q38C91_TRYB2) -  methionine--tRNA ligase from Trypanosoma brucei brucei (strain 927/4 GUTat10.1)

Seq: 773 a.a.

Struc: 517 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.6.1.1.10 - methionine--tRNA ligase.
• Reaction: tRNA(Met) + L-methionine + ATP = L-methionyl-tRNA(Met) + AMP + diphosphate

tRNA(Met) + L-methionine (Bound ligand (Het Group name = MET) corresponds exactly) + ATP = L-methionyl-tRNA(Met) + AMP + diphosphate

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

reference

DOI no: 10.1021/acsinfecdis.6b00036

Acs Infect Dis 2:399-404 (2016)

PubMed id: 27627628

5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors.

Z.Zhang, C.Y.Koh, R.M.Ranade, S.Shibata, J.R.Gillespie, M.A.Hulverson, W.Huang, J.Nguyen, N.Pendem, M.H.Gelb, C.L.Verlinde, W.G.Hol, F.S.Buckner, E.Fan.

ABSTRACT

Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase of Trypanosoma brucei. In particular, incorporating 5-fluoroimidazo[4,5-b]pyridine into inhibitors leads to central nervous system bioavailability and maintained or even improved efficacy.