Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632.

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.

journal_name

J Biochem

journal_title

Journal of biochemistry

authors

Yamaguchi H,Miwa Y,Kasa M,Kitano K,Amano M,Kaibuchi K,Hakoshima T

doi

10.1093/jb/mvj172

subject

Has Abstract

pub_date

2006-09-01 00:00:00

pages

305-11

issue

3

eissn

0021-924X

issn

1756-2651

pii

mvj172

journal_volume

140

pub_type

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