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Journal of Biochemistry Advance Access published online on August 4, 2006
Journal of Biochemistry, doi:10.1093/jb/mvj172
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© 2006 The Japanese Biochemical Society.
Received June 7, 2006
Accepted July 15, 2006

Rapid Communication

Structural Basis for Induced-Fit Binding of Rho-Kinase to the Inhibitor Y27632

Hiroto Yamaguchi 1 #, Yukiko Miwa 2 #, Miyuki Kasa 1, Ken Kitano 2, Mutsuki Amano 3, Kozo Kaibuchi 3, and Toshio Hakoshima 1 *

1 Structural Biology Laboratory, Nara Institute of Science and Technology, Keihanna Science City, Nara 630-0192, Japan; CREST, Japan Science and Technology Agency, Keihanna Science City, Nara 630-0192, Japan
2 Structural Biology Laboratory, Nara Institute of Science and Technology, Keihanna Science City, Nara 630-0192, Japan
3 Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Aichi, Japan

* To whom correspondence should be addressed.
Toshio Hakoshima, E-mail: hakosima{at}bs.naist.jp


  Abstract

Rho-kinase is a main player in the regulation of cytoskeletal events and a promising drug target in the treatment of both vascular and neurological disorders. Here we report the crystal structure of the Rho-kinase catalytic domain in complex with the specific inhibitor Y-27632. Comparison with the structure of PKA bound to this inhibitor revealed a potential induced-fit binding mode that can be accommodated by the phosphate binding loop. This binding mode resembles to that observed in the Rho-kinase-fasudil complex. A structural database search indicated that a pocket underneath the phosphate-binding loop is present that favors binding to a small aromatic ring. Introduction of such a ring group might spawn a new modification scheme of pre-existing protein kinase inhibitors for improved binding capability.

# These authors contributed equally to this work.
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