PDBsum entry 6qen

Hydrolase

PDB id: 6qen

Contents

Protein chain

240 a.a.

Ligands

J05

PO4 ×2

MPD

Metals

_NA

Waters ×213

References listed in PDB file

Key reference

• Title: 3-Oxo-β-Sultam as a sulfonylating chemotype for inhibition of serine hydrolases and activity-Based protein profiling.
• Authors: L.A.R.Carvalho, V.T.Almeida, J.A.Brito, K.M.Lum, T.F.Oliveira, R.C.Guedes, L.M.Gonçalves, S.D.Lucas, B.F.Cravatt, M.Archer, R.Moreira.
• Ref.: ACS Chem Biol, 2020, 15, 878-883. [DOI no: 10.1021/acschembio.0c00090]
• PubMed id: 32176480

Abstract

3-Oxo-β-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-β-sultam inhibitors and show, through crystallographic data, that they are regioselective sulfonylating electrophiles, covalently binding to the catalytic serine of human and porcine elastases through the sulfur atom. Application of 3-oxo-β-sultam-derived activity-based probes in a human proteome revealed their potential to label disease-related serine hydrolases and proteasome subunits. Activity-based protein profiling applications of 3-oxo-β-sultams should open up new opportunities to investigate these classes of enzymes in complex proteomes and expand the toolbox of available sulfur-based covalent protein modifiers in chemical biology.