Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil

Hiroto Yamaguchi, Miyuki Kasa, Mutsuki Amano, Kozo Kaibuchi, Toshio Hakoshima

Research output: Contribution to journalArticlepeer-review

116 Citations (Scopus)

Abstract

Rho-kinase is a key regulator of cytoskeletal events and a promising drug target in the treatment of vascular diseases and neurological disorders. Unlike other protein kinases, Rho-kinase requires both N- and C-terminal extension segments outside the kinase domain for activity, although the details of this requirement have been elusive. The crystal structure of an active Rho-kinase fragment containing the kinase domain and both the extensions revealed a head-to-head homodimer through the N-terminal extension forming a helix bundle that structurally integrates the C-terminal extension. This structural organization enables binding of the C-terminal hydrophobic motif to the N-terminal lobe, which defines the correct disposition of helix αC that is important for the catalytic activity. The bound inhibitor fasudil significantly alters the conformation and, consequently, the mode of interaction with the catalytic cleft that contains local structural changes. Thus, both kinase and drug conformational pliability and stability confer selectivity.

Original languageEnglish
Pages (from-to)589-600
Number of pages12
JournalStructure
Volume14
Issue number3
DOIs
Publication statusPublished - 03-2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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