7PQK

Co-Crystal Structure of M. tuberculosis LeuRS in Complex with the Adduct Formed by Prodrug Cmpd1 with Adenosine-monophosphate

Summary for 7PQK

• Entry DOI: 10.2210/pdb7pqk/pdb
• Descriptor: Leucine--tRNA ligase, (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: leucyl-trna synthetase, catalyses the reaction: atp + l-leucine + trna(leu) = amp + diphosphate + l-leucyl-trna(leu) leucine-trna ligase atp binding domain, ligase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 1
• Total formula weight: 25568.59

Authors

Palencia, A.,Cusack, S. (deposition date: 2021-09-17, release date: 2023-01-18, Last modification date: 2024-02-07)

Primary citation

Hoffmann, G.,Le Gorrec, M.,Mestdach, E.,Cusack, S.,Salmon, L.,Jensen, M.R.,Palencia, A.
Adenosine-Dependent Activation Mechanism of Prodrugs Targeting an Aminoacyl-tRNA Synthetase.
J.Am.Chem.Soc., 145:800-810, 2023

PubMed Abstract: Prodrugs have little or no pharmacological activity and are converted to active drugs in the body by enzymes, metabolic reactions, or through human-controlled actions. However, prodrugs promoting their chemical bioconversion without any of these processes have not been reported before. Here, we present an enzyme-independent prodrug activation mechanism by boron-based compounds (benzoxaboroles) targeting leucyl-tRNA synthetase (LeuRS), including an antibiotic that recently has completed phase II clinical trials to cure tuberculosis. We combine nuclear magnetic resonance spectroscopy and X-ray crystallography with isothermal titration calorimetry to show that these benzoxaboroles do not bind directly to their drug target LeuRS, instead they are prodrugs that activate their bioconversion by forming a highly specific and reversible LeuRS inhibition adduct with ATP, AMP, or the terminal adenosine of the tRNA. We demonstrate how the oxaborole group of the prodrugs cyclizes with the adenosine ribose at physiological concentrations to form the active molecule. This bioconversion mechanism explains the remarkably good druglike properties of benzoxaboroles showing efficacy against radically different human pathogens and fully explains the mechanism of action of these compounds. Thus, this adenosine-dependent activation mechanism represents a novel concept in prodrug chemistry that can be applied to improve the solubility, permeability and metabolic stability of challenging drugs.

PubMed: 36599057
DOI: 10.1021/jacs.2c04808

Experimental method

X-RAY DIFFRACTION (1.15 Å)