9YYO

Crystal structure of Mycobacterium tuberculosis Prolyl-tRNA synthetase in complex with ProAMS

Summary for 9YYO

• Entry DOI: 10.2210/pdb9yyo/pdb
• Descriptor: Proline--tRNA ligase, '5'-O-(N-(L-PROLYL)-SULFAMOYL)ADENOSINE, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: aminoacyl-trna synthetase protein synthesis, structural genomics, center for structural biology of infectious diseases, csbid, ligase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 4
• Total formula weight: 259377.35

Authors

Gade, P.,Maltseva, N.,Jedrejczak, R.,Michalska, K.,Joachimiak, A.,Center for Structural Biology of Infectious Diseases (CSBID) (deposition date: 2025-10-29, release date: 2026-11-04)

Primary citation

Gade, P.,Michalska, K.,Zitko, J.,Wower, J.,Maltseva, N.,Pallabothula, V.S.K.,Jedrzejczak, R.,Joachimiak, A.
Atomic-Level Structures Reveal How a Repurposed 3‐Aminopyrazine-2-carboxamide Scaffold Inhibits Mycobacterium tuberculosis Prolyl-tRNA Synthetase.
Acs Omega, 11:57583-57594, 2026

PubMed Abstract: Tuberculosis (TB) is again the world's leading cause of death from a single infectious agent. Aminoacyl-tRNA synthetases are essential for protein synthesis and are promising drug targets because bacterial and human enzymes differ. We repurposed a human prolyl-tRNA synthetase (ProRS) inhibitor scaffold, 3-aminopyrazine-2-carboxamide, to inhibit the enzyme (ProRS). These derivatives show strong activity against multidrug-resistant strains and are not cytotoxic to HepG2 cells. We determined high-resolution crystal structures of ProRS bound to six derivatives to define their binding modes. The compounds bind in the ATP site and trigger local conformational changes that disrupt the proline pocket, supporting a dual-site mechanism of inhibition. Comparison with human cytosolic and mitochondrial ProRS reveals differences in active-site residues, electrostatics, and dynamics that explain species selectivity. Together, these structures provide a framework for designing next-generation, -selective ProRS inhibitors as new antitubercular candidates.

PubMed: 42825133
DOI: 10.1021/acsomega.6c04844

Experimental method

X-RAY DIFFRACTION (2.71 Å)