PDBsum entry 4tpt

Transferase/transferase inhibitor

PDB id: 4tpt

Contents

Protein chains

279 a.a.

Ligands

35H ×2

Waters ×30

PDB id:

4tpt

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of the human limk2 kinase domain in complex with a non-atp competitive inhibitor

Structure:

Lim domain kinase 2. Chain: a, b. Fragment: kinase domain (unp residues 330-632). Synonym: limk-2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: limk2. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469

Resolution:

2.60Å R-factor: 0.223 R-free: 0.274

Authors:

N.C.Goodwin,G.Cianchetta,B.L.Hamman,H.A.Burgoon,J.Healy,S.Mabon, E.D.Strobel,S.Wang,D.B.Rawlins

Key ref:

N.C.Goodwin et al. (2015). Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation. Acs Med Chem Lett, 6, 53-57. PubMed id: 25589930 DOI: 10.1021/ml500242y

Date:

09-Jun-14 Release date: 22-Oct-14

Protein chains

P53671  (LIMK2_HUMAN) -  LIM domain kinase 2 from Homo sapiens

Seq: 638 a.a.

Struc: 279 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/ml500242y

Acs Med Chem Lett 6:53-57 (2015)

PubMed id: 25589930

Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.

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.

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.