Protein kinase a in complex with rho-kinase inhibitors Y-27632, fasudil, and H-1152P: Structural basis of selectivity
Protein kinase a in complex with rho-kinase inhibitors Y-27632, fasudil, and H-1152P: Structural basis of selectivity
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DOI：
10.1016/j.str.2003.11.002
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发表时间：
2003-12-01
期刊：
影响因子：
5.7
通讯作者：
Bossemeyer, D
中科院分区：
文献类型：
--
作者：
Breitenlechner, C;Gassel, M;Bossemeyer, D
蛋白激酶需要严格的失活以防止虚假的细胞信号传导;过度活性可导致癌症或其他疾病，并且需要选择性抑制以进行治疗。Rho激酶参与肿瘤侵袭、细胞粘附、平滑肌收缩和粘着斑纤维的形成等过程，如使用抑制剂Y-27632所揭示的。另一种Rho激酶抑制剂，HA-1077或法舒地尔，目前用于治疗脑血管痉挛;相关的纳摩尔抑制剂H-1152 P提高了其选择性和效力。我们已经确定了HA-1077，H-1152 P和Y-27632与蛋白激酶A（PKA）作为替代激酶的复合物的晶体结构，以分析Rho激酶抑制剂的结合特性。PKA和Rho-激酶之间的保守特征涉及关键的结合相互作用，而Rho-激酶特有的ATP结合口袋处的残基的组合可以解释抑制剂的Rho-激酶选择性。此外，第二个H-1152 P结合位点可能指向PKA调节结构域相互作用调节剂。
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.