6R1V

Solution structure of sortase A from S. aureus in complex with 2-(aminomethyl)-3-hydroxy-4H-pyran-4-one based prodrug

Summary for 6R1V

• Entry DOI: 10.2210/pdb6r1v/pdb
• NMR Information: BMRB: 34379
• Descriptor: Sortase A, 6-(hydroxymethyl)-3-oxidanyl-2-(thiophen-3-ylmethyl)pyran-4-one (2 entities in total)
• Functional Keywords: inhibitor, covalent complex, prodrug, hydrolase
• Biological source: Staphylococcus aureus subsp. aureus NCTC 8325
• Total number of polymer chains: 1
• Total formula weight: 17063.32

Authors

Jaudzems, K.,Leonchiks, A. (deposition date: 2019-03-15, release date: 2020-01-22, Last modification date: 2024-10-16)

Primary citation

Jaudzems, K.,Kurbatska, V.,Je Kabsons, A.,Bobrovs, R.,Rudevica, Z.,Leonchiks, A.
Targeting Bacterial Sortase A with Covalent Inhibitors: 27 New Starting Points for Structure-Based Hit-to-Lead Optimization.
Acs Infect Dis., 6:186-194, 2020

PubMed Abstract: Because of its essential role as a bacterial virulence factor, enzyme sortase A (SrtA) has become an attractive target for the development of new antivirulence drugs against Gram-positive infections. Here we describe 27 compounds identified as covalent inhibitors of SrtA by screening a library of approximately 50 000 compounds using a FRET assay followed by NMR-based validation and binding reversibility analysis. Nineteen of these compounds displayed only moderate to weak cytotoxicity, with CC against NIH 3T3 mice fibroblast cells ranging from 12 to 740 μM. Analysis using covalent docking suggests that the inhibitors initially associate via hydrophobic interactions, followed by covalent bond formation between the SrtA active site cysteine and an electrophilic center of the inhibitor. The compounds represent good starting points that have the potential to be developed into broad spectrum antivirulence agents as exemplified by hit-to-lead optimization of one of the compounds.

PubMed: 31724850
DOI: 10.1021/acsinfecdis.9b00265

Experimental method

SOLUTION NMR