Inhibiting AMPylation: A Novel Screen To Identify the First Small Molecule Inhibitors of Protein AMPylation
Year: 2013
Type: article
Abstract: Enzymatic transfer of the AMP portion of ATP to substrate proteins has recently been described as an essential mechanism of bacterial infection for several pathogens. The first AMPylator to be discovered, VopS from Vibrio parahemolyticus, catalyzes the transfer of AMP onto the host GTPases Cdc42 and Rac1. Modification of these proteins disrupts downstream signaling events, contributing to cell rounding and apoptosis, and recent studies have suggested that blocking AMPylation may be an effective route to stop infection. To date, however, no small molecule inhibitors have been discovered for any of the AMPylators. Therefore, we developed a fluorescence-polarization-based high-throughput screening assay and used it to discover the first inhibitors of protein AMPylation. Herein we report the discovery of the first small molecule VopS inhibitors (e.g., calmidazolium, GW7647, and MK886) with Ki's ranging from 6 to 50 μM and upward of 30-fold selectivity versus HYPE, the only known human AMPylator.
Source: ACS Chemical Biology
DOI: 10.1021/cb4006886
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: The Comprehensive Center for Chemical Probe Discovery and Optimization at Scripps, Biochemical Characterization of Yersinia Effector YopJ, G468229746, G6296143508, Acquisition of a LTQ/Orbitrap MS to advance the study of protein dynamics, Analysis of an orchestrated cell death mediated by Vibrio parahaemolytics T3SS1, Development of H/D exchange technology for the study of large protein complexes
OpenAlex ID: W2081361850