4kp0

Crystal Structure of the human Chymase with TJK002

spinqualitylabelsall models 4kp0, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4kp0 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: KPK Gene: CMA1 (Homo sapiens) Activity: Chymase, with EC number 3.4.21.39 Resources: FirstGlance, OCA, RCSB, PDBsum Function [CMA1_HUMAN] Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion. Publication Abstract from PubMed The crystal structure of human chymase complexed with a novel benzimidazole inhibitor, TJK002, was determined at 2.8 A resolution. The X-ray crystallographic study shows that the benzimidazole inhibitor forms a non-covalent interaction with the catalytic domain of human chymase. The hydrophobic fragment of the inhibitor occupies the S1 pocket. The carboxylic acid group of the inhibitor forms hydrogen bonds with the imidazole N() atom of His57 and/or the O(gamma) atom of Ser195 which are members of the catalytic triad. This imidazole ring of His57 induces pi-pi stacking to the benzene ring of the benzimidazole scaffold as P2 moiety. Fragment molecular orbital calculation of the atomic coordinates by X-ray crystallography shows that this imidazole ring of His57 could be protonated with the carboxyl group of Asp102 or hydroxyl group of Ser195 and the stacking interaction is stabilized. A new drug design strategy is proposed where the stacking to the protonated imidazole of the drug target protein with the benzimidazole scaffold inhibitor causes unpredicted potent inhibitory activity for some enzymes. Crystal structure of a complex of human chymase with its benzimidazole derived inhibitor.,Matsumoto Y, Kakuda S, Koizumi M, Mizuno T, Muroga Y, Kawamura T, Takimoto-Kamimura M J Synchrotron Radiat. 2013 Nov;20(Pt 6):914-8. doi: 10.1107/S0909049513020748., Epub 2013 Sep 25. PMID:24121339 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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