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Journal of Biochemistry Advance Access originally published online on August 4, 2006
Journal of Biochemistry 2006 140(3):305-311; doi:10.1093/jb/mvj172
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© 2006 The Japanese Biochemical Society.

Rapid Communication

Structural Basis for Induced-Fit Binding of Rho-Kinase to the Inhibitor Y-27632

Hiroto Yamaguchi1,2,*, Yukiko Miwa1,*, Miyuki Kasa1,2, Ken Kitano1, Mutsuki Amano3, Kozo Kaibuchi3 and Toshio Hakoshima1,2,{dagger}

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

{dagger} To whom correspondence should be addressed. Tel: +81-743-72-5570, Fax: +81-743-72-5579, E-mail: hakosima{at}bs.naist.jp

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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