1ZG9

Crystal Structure of 5-{[amino(imino)methyl]amino}-2-(sulfanylmethyl)pentanoic acid Bound to Activated Porcine Pancreatic Carboxypeptidase B


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.206 

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This is version 1.3 of the entry. See complete history


Literature

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

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

(2005) Biochemistry 44: 9339-9347

  • DOI: https://doi.org/10.1021/bi0501941
  • Primary Citation of Related Structures:  
    1Z5R, 1ZG7, 1ZG8, 1ZG9

  • 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.


  • Organizational Affiliation

    Berlex Biosciences, 2600 Hilltop Drive, P.O. Box 4099, Richmond, California 94804-0099, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
procarboxypeptidase B
A, B, C
306Sus scrofaMutation(s): 0 
EC: 3.4.17.2
UniProt
Find proteins for P09955 (Sus scrofa)
Explore P09955 
Go to UniProtKB:  P09955
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09955
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.206 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.839α = 90
b = 102.484β = 90
c = 136.157γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
X-PLORrefinement
CCP4data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-07-12
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description