Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632.
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.
Yamaguchi
Hiroto
H
Structural Biology Laboratory, Nara Institute of Science and Technology, and CREST, Japan .
Miwa
Yukiko
Y
Kasa
Miyuki
M
Kitano
Ken
K
Amano
Mutsuki
M
Kaibuchi
Kozo
K
Hakoshima
Toshio
T
D000577:Amides / Q000737:chemistry*; D003461:Crystallography; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry*; D013379:Substrate Specificity; D054460:rho-Associated Kinases
D000577:Amides; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases