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

C Breitenlechner, M Gaßel, H Hidaka, V Kinzel… - Structure, 2003 - cell.com
C Breitenlechner, M Gaßel, H Hidaka, V Kinzel, R Huber, RA Engh, D Bossemeyer
Structure, 2003cell.com
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 …
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.
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