Protein Kinase A in Complex with Rho-Kinase Inhibitors Y-27632, Fasudil, and H-1152P: Structural Basis of Selectivity
作者： Christine Breitenlechner , Michael Gaßel , Hiroyoshi Hidaka , Volker Kinzel , Robert Huber
DOI: 10.1016/J.STR.2003.11.002
关键词:
摘要: 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, formation of focal adhesion fibers, revealed using inhibitor Y-27632. Another inhibitor, HA-1077 Fasudil, currently used the treatment cerebral vasospasm; related nanomolar H-1152P improves on its selectivity potency. We have determined crystal structures HA-1077, H-1152P, Y-27632 complexes with protein kinase A (PKA) a surrogate analyze binding properties. Features conserved between PKA are key interactions, while combination residues at ATP pocket that unique may explain inhibitors' selectivity. Further, second site potentially points toward regulatory domain interaction modulators.
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