4LV0: Ampc Beta-lactamase In Complex With M-aminophenyl Boronic Acid

Chemical probes that form a covalent bond with a protein target often show enhanced selectivity, potency and utility for biological studies. Despite these advantages, protein-reactive compounds are usually avoided in high-throughput screening campaigns. Here we describe a general method (DOCKovalent) for screening large virtual libraries of electrophilic small molecules. We apply this method prospectively to discover reversible covalent fragments that target distinct protein nucleophiles, including the catalytic serine of AmpC beta-lactamase and noncatalytic cysteines in RSK2, MSK1 and JAK3 kinases. We identify submicromolar to low-nanomolar hits with high ligand efficiency, cellular activity and selectivity, including what are to our knowledge the first reported reversible covalent inhibitors of JAK3. Crystal structures of inhibitor complexes with AmpC and RSK2 confirm the docking predictions and guide further optimization. As covalent virtual screening may have broad utility for the rapid discovery of chemical probes, we have made the method freely available through an automated web server (http://covalent.docking.org/).
PDB ID: 4LV0Download
MMDB ID: 121888
PDB Deposition Date: 2013/7/25
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 1.65  Å
Source Organism:
Similar Structures:
Biological Unit for 4LV0: monomeric; determined by author and by software (PISA)
Molecular Components in 4LV0
Label Count Molecule
Protein (1 molecule)
Beta-lactamase(Gene symbol: ampC)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB