1PJP

THE 2.2 A CRYSTAL STRUCTURE OF HUMAN CHYMASE IN COMPLEX WITH SUCCINYL-ALA-ALA-PRO-PHE-CHLOROMETHYLKETONE

Summary for 1PJP

• Entry DOI: 10.2210/pdb1pjp/pdb
• Related PRD ID: PRD_000381
• Descriptor: Chymase, SUCCINYL-ALA-ALA-PRO-PHE-CHLOROMETHYLKETONE INHIBITOR, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: human chymase, serine proteinase, dipeptidyl carboxypeptidase, angiotensin, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 26038.70

Authors

Pereira, P.J.B.,Wang, Z.M.,Rubin, H.,Huber, R.,Bode, W.,Schechter, N.M.,Strobl, S. (deposition date: 1998-09-07, release date: 1999-03-02, Last modification date: 2024-04-24)

Primary citation

Pereira, P.J.,Wang, Z.M.,Rubin, H.,Huber, R.,Bode, W.,Schechter, N.M.,Strobl, S.
The 2.2 A crystal structure of human chymase in complex with succinyl-Ala-Ala-Pro-Phe-chloromethylketone: structural explanation for its dipeptidyl carboxypeptidase specificity.
J.Mol.Biol., 286:163-173, 1999

PubMed Abstract: Human chymase (HC) is a chymotrypsin-like serine proteinase expressed by mast cells. The 2.2 A crystal structure of HC complexed to the peptidyl inhibitor, succinyl-Ala-Ala-Pro-Phe-chloromethylketone (CMK), was solved and refined to a crystallographic R-factor of 18.4 %. The HC structure exhibits the typical folding pattern of a chymotrypsin-like serine proteinase, and shows particularly similarity to rat chymase 2 (rat mast cell proteinase II) and human cathepsin G. The peptidyl-CMK inhibitor is covalently bound to the active-site residues Ser195 and His57; the peptidyl moiety juxtaposes the S1 entrance frame segment 214-217 by forming a short antiparallel beta-sheet. HC is a highly efficient angiotensin-converting enzyme. Modeling of the chymase-angiotensin I interaction guided by the geometry of the bound chloromethylketone inhibitor indicates that the extended substrate binding site contains features that may generate the dipeptidyl carboxypeptidase-like activity needed for efficient cleavage and activation of the hormone. The C-terminal carboxylate group of angiotensin I docked into the active-site cleft, with the last two residues extending beyond the active site, is perfectly localized to make a favorable hydrogen bond and salt bridge with the amide nitrogen of the Lys40-Phe41 peptide bond and with the epsilon-ammonium group of the Lys40 side-chain. This amide positioning is unique to the chymase-related proteinases, and only chymases from primates possess a Lys residue at position 40. Thus, the structure conveniently explains the preferred conversion of angiotensin I to angiotensin II by human chymase.

PubMed: 9931257
DOI: 10.1006/jmbi.1998.2462

Experimental method

X-RAY DIFFRACTION (2.2 Å)