PDBsum entry 1zg9

Hydrolase

PDB id: 1zg9

Contents

Protein chains

305 a.a. *

Ligands

L06 ×3

Metals

_ZN ×3

Waters ×468

* Residue conservation analysis

PDB id:

1zg9

Name:

Hydrolase

Title:

Crystal structure of 5-{[amino(imino)methyl]amino}-2-(sulfanylmethyl) pentanoic acid bound to activated porcine pancreatic carboxypeptidase b

Structure:

Procarboxypeptidase b. Chain: a, b, c. Fragment: catalytic domain. Ec: 3.4.17.2

Source:

Sus scrofa. Pig. Organism_taxid: 9823

Resolution:

2.00Å R-factor: 0.203 R-free: 0.272

Authors:

M.Adler,J.Bryant,B.Buckman,I.Islam,B.Larsen,S.Finster,L.Kent,K.May, R.Mohan,S.Yuan,M.Whitlow

Key ref:

M.Adler et al. (2005). Crystal structures of potent thiol-based inhibitors bound to carboxypeptidase B. Biochemistry, 44, 9339-9347. PubMed id: 15982000 DOI: 10.1021/bi0501941

Date:

20-Apr-05 Release date: 12-Jul-05

Protein chains

P09955  (CBPB1_PIG) -  Carboxypeptidase B from Sus scrofa

Seq: 416 a.a.

Struc: 305 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.17.2 - carboxypeptidase B.
• Reaction: Peptidyl-L-lysine(or L-arginine) + H(2)O = peptide + L-lysine(or L- arginine)
• Cofactor: Zn(2+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

DOI no: 10.1021/bi0501941

Biochemistry 44:9339-9347 (2005)

PubMed id: 15982000

Crystal structures of potent thiol-based inhibitors bound to carboxypeptidase B.

M.Adler, J.Bryant, B.Buckman, I.Islam, B.Larsen, S.Finster, L.Kent, K.May, R.Mohan, S.Yuan, M.Whitlow.

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.