1ZG8

Crystal Structure of (R)-2-(3-{[amino(imino)methyl]amino}phenyl)-3-sulfanylpropanoic acid Bound to Activated Porcine Pancreatic Carboxypeptidase B

1ZG8 の概要

• エントリーDOI: 10.2210/pdb1zg8/pdb
• 関連するPDBエントリー: 1kwm 1nsa 1z5r 1zg7 1zg9
• 分子名称: procarboxypeptidase B, ZINC ION, (2R)-2-(3-{[AMINO(IMINO)METHYL]AMINO}PHENYL)-3-SULFANYLPROPANOIC ACID, ... (4 entities in total)
• 機能のキーワード: carboxypeptidase b, exopeptidase, thiol based inhibitor, hydrolase
• 由来する生物種: Sus scrofa (pig)
• 細胞内の位置: Secreted: P09955
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 105133.69

構造登録者

Adler, M.,Bryant, J.,Buckman, B.,Islam, I.,Larsen, B.,Finster, S.,Kent, L.,May, K.,Mohan, R.,Yuan, S.,Whitlow, M. (登録日: 2005-04-20, 公開日: 2005-07-12, 最終更新日: 2024-10-30)

主引用文献

Adler, M.,Bryant, J.,Buckman, B.,Islam, I.,Larsen, B.,Finster, S.,Kent, L.,May, K.,Mohan, R.,Yuan, S.,Whitlow, M.
Crystal structures of potent thiol-based inhibitors bound to carboxypeptidase b.
Biochemistry, 44:9339-9347, 2005

PubMed Abstract: This paper presents the crystal structure of porcine pancreatic carboxypeptidase B (pp-CpB) in complex with a variety of thiol-based inhibitors that were developed as antagonists of activated thrombin-activatable fibrinolysis inhibitor (TAFIa). Recent studies have indicated that a selective inhibitor of TAFIa could enhance the efficacy of existing thrombolytic agents for the treatment of acute myocardial infarction, one of the most prevalent forms of heart attacks. Unfortunately, activated TAFIa rapidly degrades in solution and cannot be used for crystallographic studies. In contrast, porcine pancreatic CpB is stable at room temperature and is available from commercial sources. Both pancreatic CpB and TAFIa are zinc-based exopeptidases, and the proteins share a 47% sequence identity. The homology improves considerably in the active site where nearly all of the residues are conserved. The inhibitors used in this study were designed to mimic a C-terminal arginine residue, one of the natural substrates of TAFIa. The X-ray structures show that the thiol group chelates the active site zinc, the carboxylic acid forms a salt bridge to Arg145, and the guanidine group forms two hydrogen bonds to Asp255. A meta-substituted phenyl was introduced into our inhibitors to reduce conformational freedom. This modification vastly improved the selectivity of compounds against other exopeptidases that cleave basic residues. Comparisons between structures indicate that selectivity derives from the interaction between the guanidine group in the inhibitors and an acidic active site residue. The location of this acidic residue is not conserved in the various carboxypeptidases.

PubMed: 15982000
DOI: 10.1021/bi0501941

実験手法

X-RAY DIFFRACTION (2 Å)