4KP0

Crystal Structure of the human Chymase with TJK002

Summary for 4KP0

• Entry DOI: 10.2210/pdb4kp0/pdb
• Descriptor: Chymase, 4-({1-[(4-methyl-1-benzothiophen-3-yl)methyl]-1H-benzimidazol-2-yl}sulfanyl)butanoic acid (3 entities in total)
• Functional Keywords: hydrolase, protease, serine protease, benzimidazole, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P23946
• Total number of polymer chains: 1
• Total formula weight: 25463.50

Authors

Kakuda, S.,Takimoto-Kamimura, M. (deposition date: 2013-05-12, release date: 2013-10-30, Last modification date: 2023-11-08)

Primary citation

Matsumoto, Y.,Kakuda, S.,Koizumi, M.,Mizuno, T.,Muroga, Y.,Kawamura, T.,Takimoto-Kamimura, M.
Crystal structure of a complex of human chymase with its benzimidazole derived inhibitor
J.SYNCHROTRON RADIAT., 20:914-918, 2013

PubMed Abstract: The crystal structure of human chymase complexed with a novel benzimidazole inhibitor, TJK002, was determined at 2.8 Å 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(ℇ) atom of His57 and/or the O(γ) atom of Ser195 which are members of the catalytic triad. This imidazole ring of His57 induces π-π 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.

PubMed: 24121339
DOI: 10.1107/S0909049513020748

Experimental method

X-RAY DIFFRACTION (2.8 Å)