4k2y | pdb_00004k2y

Crystal Structure of Human Chymase in Complex with Fragment Inhibitor 6-chloro-1,3-dihydro-2H-indol-2-one

spinqualitylabelsall models 4k2y, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4k2y is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ES2, NAG, ZN Related: 3s0n, 4k5z, 4k60, 4k69 Gene: CMA1, CYH, CYM (Homo sapiens) Activity: Chymase, with EC number 3.4.21.39 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-Ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100 fold selective over cathepsin G, and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from. Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies.,Taylor SJ, Padyana AK, Abeywardane A, Liang S, Hao MH, De Lombaert S, Proudfoot JR, Farmer BS, Li X, Collins B, Albaugh DR, Martin L, Hill-Drzewi M, Pullen SS, Takahashi H J Med Chem. 2013 May 9. PMID:23659209 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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