PDBsum entry 4tpt

Transferase/transferase inhibitor

PDB id: 4tpt

Contents

Protein chains

279 a.a.

Ligands

35H ×2

Waters ×30

References listed in PDB file

Key reference

• Title: Discovery of a type III inhibitor of lim kinase 2 that binds in a dfg-Out conformation.
• Authors: N.C.Goodwin, G.Cianchetta, H.A.Burgoon, J.Healy, R.Mabon, E.D.Strobel, J.Allen, S.Wang, B.D.Hamman, D.B.Rawlins.
• Ref.: Acs Med Chem Lett, 2015, 6, 53-57. [DOI no: 10.1021/ml500242y]
• PubMed id: 25589930

Abstract

The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be noncompetitive with ATP, suggesting allosteric inhibition. X-ray crystallography confirmed that these sulfonamides are a rare example of a type III kinase inhibitor that binds away from the highly conserved hinge region and instead resides in the hydrophobic pocket formed in the DFG-out conformation of the kinase, thus accounting for the high level of selectivity observed.