3V8S

Human RHO-ASSOCIATED PROTEIN KINASE 1 (ROCK 1) IN COMPLEX WITH INDAZOLE DERIVATIVE (COMPOUND 18)

Summary for 3V8S

• Entry DOI: 10.2210/pdb3v8s/pdb
• Descriptor: Rho-associated protein kinase 1, 1-(1H-indazol-5-yl)-3-(2-phenylethyl)urea (3 entities in total)
• Functional Keywords: kinase, dimerization, myosin, transferase, inhibitor, 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: 191063.94

Authors

Martin, M.P.,Zhu, J.-Yi.,Schonbrunn, E. (deposition date: 2011-12-23, release date: 2012-02-08, Last modification date: 2023-09-13)

Primary citation

Li, R.,Martin, M.P.,Liu, Y.,Wang, B.,Patel, R.A.,Zhu, J.Y.,Sun, N.,Pireddu, R.,Lawrence, N.J.,Li, J.,Haura, E.B.,Sung, S.S.,Guida, W.C.,Schonbrunn, E.,Sebti, S.M.
Fragment-based and structure-guided discovery and optimization of rho kinase inhibitors.
J.Med.Chem., 55:2474-2478, 2012

PubMed Abstract: Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC(50) = 650 nM) and ROCK2 (IC(50) = 670 nM), whereas compound 24 was more selective for ROCK2 (IC(50) = 100 nM) over ROCK1 (IC(50) = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.

PubMed: 22272748
DOI: 10.1021/jm201289r

Experimental method

X-RAY DIFFRACTION (2.286 Å)