4TPT

Crystal Structure of the Human LIMK2 Kinase Domain In Complex With a Non-ATP Competitive Inhibitor

Summary for 4TPT

• Entry DOI: 10.2210/pdb4tpt/pdb
• Descriptor: LIM domain kinase 2, N-{4-[(1S)-1,2-dihydroxyethyl]benzyl}-N-methyl-4-(phenylsulfamoyl)benzamide (3 entities in total)
• Functional Keywords: limk2 kinase, dfg inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform LIMK2a: Cytoplasm. Isoform LIMK2b: Cytoplasm: P53671
• Total number of polymer chains: 2
• Total formula weight: 70043.89

Authors

Goodwin, N.C.,Cianchetta, G.,Hamman, B.L.,Burgoon, H.A.,Healy, J.,Mabon, S.,Strobel, E.D.,Wang, S.,Rawlins, D.B. (deposition date: 2014-06-09, release date: 2014-10-22, Last modification date: 2024-10-23)

Primary citation

Goodwin, N.C.,Cianchetta, G.,Burgoon, H.A.,Healy, J.,Mabon, R.,Strobel, E.D.,Allen, J.,Wang, S.,Hamman, B.D.,Rawlins, D.B.
Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.
Acs Med.Chem.Lett., 6:53-57, 2015

PubMed 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.

PubMed: 25589930
DOI: 10.1021/ml500242y

Experimental method

X-RAY DIFFRACTION (2.6 Å)