1Q8W

The Catalytic Subunit of cAMP-dependent Protein Kinase in Complex with Rho-kinase Inhibitor Fasudil (HA-1077)

Summary for 1Q8W

• Entry DOI: 10.2210/pdb1q8w/pdb
• Related: 1Q8T 1Q8U
• Descriptor: cAMP-dependent protein kinase, alpha-catalytic subunit, cAMP-dependent protein kinase inhibitor, alpha form, 5-(1,4-DIAZEPAN-1-SULFONYL)ISOQUINOLINE, ... (4 entities in total)
• Functional Keywords: kinase-inhibitor-complex, phosphotransferase/inhibitor, camp, phosphorylation, serine/threonine-protein kinase, atp-binding, pka, rho-kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Bos taurus (cattle); More
• Cellular location: Cytoplasm: P00517
• Total number of polymer chains: 2
• Total formula weight: 43304.17

Authors

Breitenlechner, C.,Gassel, M.,Hidaka, H.,Kinzel, V.,Huber, R.,Engh, R.A.,Bossemeyer, D. (deposition date: 2003-08-22, release date: 2003-12-16, Last modification date: 2011-07-13)

Primary citation

Breitenlechner, C.,Gassel, M.,Hidaka, H.,Kinzel, V.,Huber, R.,Engh, R.A.,Bossemeyer, D.
Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity.
Structure, 11:1595-1607, 2003

PubMed Abstract: Protein kinases require strict inactivation to prevent spurious cellular signaling; overactivity can cause cancer or other diseases and necessitates selective inhibition for therapy. Rho-kinase is involved in such processes as tumor invasion, cell adhesion, smooth muscle contraction, and formation of focal adhesion fibers, as revealed using inhibitor Y-27632. Another Rho-kinase inhibitor, HA-1077 or Fasudil, is currently used in the treatment of cerebral vasospasm; the related nanomolar inhibitor H-1152P improves on its selectivity and potency. We have determined the crystal structures of HA-1077, H-1152P, and Y-27632 in complexes with protein kinase A (PKA) as a surrogate kinase to analyze Rho-kinase inhibitor binding properties. Features conserved between PKA and Rho-kinase are involved in the key binding interactions, while a combination of residues at the ATP binding pocket that are unique to Rho-kinase may explain the inhibitors' Rho-kinase selectivity. Further, a second H-1152P binding site potentially points toward PKA regulatory domain interaction modulators.

PubMed: 14656443
DOI: 10.1016/j.str.2003.11.002

Experimental method

X-RAY DIFFRACTION (2.2 Å)