Structural basis for selectivity of the isoquinoline sulfonamide family of protein kinase inhibitors

Xu, R. M., Carmel, G., Kuret, J., Cheng, X. (June 1996) Structural basis for selectivity of the isoquinoline sulfonamide family of protein kinase inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 93 (13). pp. 6308-13. ISSN 0027-8424

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A large family of isoquinoline sulfonamide compounds inhibits protein kinases by competing with adenosine triphosphates(ATP), yet interferes little with the activity of other ATP-using enzymes such as ATPases and adenylate cyclases. One such compound, N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CK17), is selective for casein kinase-1 isolated from a variety of sources. Here we report the crystal structure of the catalytic domain of Schizosaccharomyces pombe casein kinase-1 complexed with CK17, refined to a crystallographic R-factor of 17.8% at 2.5 angstrom resolution. The structure provides new insights into the mechanism of the ATP-competing inhibition and the origin of their selectivity toward different protein kinases. Selectivity for protein kinases versus other enzymes is achieved by hydrophobic contacts and the hydrogen bond with isoquinoline ring. We propose that the hydrogen bond involving the ring nitrogen-2 atom of the isoquinoline must be preserved, but that the ring can flip depending on the chemical substituents at ring positions 5 and 8. Selectivity for individual members of the protein kinase family is achieved primarily by interactions with these substituents.

Item Type: Paper
Uncontrolled Keywords: Adenosine Triphosphate/metabolism Amino Acid Sequence Crystallography, X-Ray Enzyme Inhibitors/chemistry/ pharmacology Hydrogen Bonding Isoquinolines/chemistry/metabolism/ pharmacology Molecular Sequence Data Molecular Structure Protein Kinase Inhibitors Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Structure-Activity Relationship Sulfonamides
Subjects: bioinformatics > genomics and proteomics > small molecules > ATP
bioinformatics > genomics and proteomics > design > amino acid design
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > Protein kinase C
Investigative techniques and equipment > x ray crystallography
CSHL Authors:
Communities: CSHL labs > Xu lab
Depositing User: Kathleen Darby
Date: 25 June 1996
Date Deposited: 12 May 2014 17:11
Last Modified: 13 Sep 2019 16:15
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