3TV7

Human Rho-associated protein kinase 1 (ROCK 1) in COMPLEX WITH RKI1342

Summary for 3TV7

• Entry DOI: 10.2210/pdb3tv7/pdb
• Descriptor: Rho-associated protein kinase 1, 1-[(1R)-1-(3-methoxyphenyl)ethyl]-3-(4-pyridin-4-yl-1,3-thiazol-2-yl)urea, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: kinase, dimer, dimerization, myosin, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q13464
• Total number of polymer chains: 4
• Total formula weight: 191546.55

Authors

Martin, M.P.,Zhu, J.-Y.,Schonbrunn, E. (deposition date: 2011-09-19, release date: 2012-02-15, Last modification date: 2023-09-13)

Primary citation

Pireddu, R.,Forinash, K.D.,Sun, N.N.,Martin, M.P.,Sung, S.S.,Alexander, B.,Zhu, J.Y.,Guida, W.C.,Schonbrunn, E.,Sebti, S.M.,Lawrence, N.J.
Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2).
Medchemcomm, 3:699-709, 2012

PubMed Abstract: Potent ROCK inhibitors of a new class of 1-benzyl-3-(4-pyridylthiazol-2-yl)ureas have been identified. Remarkable differences in activity were observed for ureas bearing a benzylic stereogenic center. Derivatives with hydroxy, methoxy and amino groups at the meta position of the phenyl ring give rise to the most potent inhibitors (low nM). Substitutions at the para position result in substantial loss of potency. Changes at the benzylic position are tolerated resulting in significant potency in the case of methyl and methylenehydroxy groups. X-Ray crystallography was used to establish the binding mode of this class of inhibitors and provides an explanation for the observed differences of the enantiomer series. Potent inhibition of ROCK in human lung cancer cells was shown by suppression of the levels of phosphorylation of the ROCK substrate MYPT-1.

PubMed: 23275831
DOI: 10.1039/C2MD00320A

Experimental method

X-RAY DIFFRACTION (2.75 Å)