Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity.

Abstract

Protein kinases require strict inactivation to prevent spurious cellular signaling; overactivity can cause cancer or other diseases and necessitates selective inhibition for therapy. Rho-kinase is involved in such processes as tumor invasion, cell adhesion, smooth muscle contraction, and formation of focal adhesion fibers, as revealed using inhibitor Y-27632. Another Rho-kinase inhibitor, HA-1077 or Fasudil, is currently used in the treatment of cerebral vasospasm; the related nanomolar inhibitor H-1152P improves on its selectivity and potency. We have determined the crystal structures of HA-1077, H-1152P, and Y-27632 in complexes with protein kinase A (PKA) as a surrogate kinase to analyze Rho-kinase inhibitor binding properties. Features conserved between PKA and Rho-kinase are involved in the key binding interactions, while a combination of residues at the ATP binding pocket that are unique to Rho-kinase may explain the inhibitors' Rho-kinase selectivity. Further, a second H-1152P binding site potentially points toward PKA regulatory domain interaction modulators.

• Authors: Christine Breitenlechner, Michael Gassel, Hiroyoshi Hidaka, Volker Kinzel, Robert Huber, Richard A Engh, Dirk Bossemeyer
• Journal: Structure (London, England : 1993) (Structure) Vol. 11 Issue 12 Pg. 1595-607 (Dec 2003) ISSN: 0969-2126 [Print] United States
• PMID: 14656443 (Publication Type: Journal Article)

Chemical References

• 2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine
• Amides
• Enzyme Inhibitors
• Pyridines
• Recombinant Proteins
• Y 27632
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• Adenosine Triphosphate
• Cyclic AMP-Dependent Protein Kinases
• fasudil
• Glycine

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Adenosine Triphosphate (chemistry)
• Amides (pharmacology)
• Amino Acid Sequence
• Animals
• Binding Sites
• Cattle
• Cell Adhesion
• Crystallography, X-Ray
• Cyclic AMP-Dependent Protein Kinases (chemistry)
• Electrons
• Enzyme Inhibitors (pharmacology)
• Escherichia coli (metabolism)
• Glycine (chemistry)
• Kinetics
• Models, Chemical
• Models, Molecular
• Molecular Sequence Data
• Muscle Contraction
• Muscle, Smooth (metabolism)
• Protein Binding
• Protein Conformation
• Protein Structure, Tertiary
• Pyridines (pharmacology)
• Recombinant Proteins (chemistry)
• Sequence Homology, Amino Acid