2PJ9

CRYSTAL STRUCTURE OF ACTIVATED PORCINE PANCREATIC CARBOXYPEPTIDASE B 2-(3-Aminomethyl-phenyl)-3-{[(R)-1-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-2-methyl-propyl]-hydroxy-phosphinoyl}-propionic acid COMPLEX


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.56 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.217 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structures of potent selective peptide mimetics bound to carboxypeptidase B.

Adler, M.Buckman, B.Bryant, J.Chang, Z.Chu, K.Emayan, K.Hrvatin, P.Islam, I.Morser, J.Sukovich, D.West, C.Yuan, S.Whitlow, M.

(2008) Acta Crystallogr D Biol Crystallogr 64: 149-157

  • DOI: https://doi.org/10.1107/S0907444907057228
  • Primary Citation of Related Structures:  
    2PIY, 2PIZ, 2PJ0, 2PJ1, 2PJ2, 2PJ3, 2PJ4, 2PJ5, 2PJ6, 2PJ7, 2PJ8, 2PJ9, 2PJA, 2PJB, 2PJC

  • PubMed Abstract: 

    This article reports the crystal structures of inhibitors of the functional form of thrombin-activatable fibrinolysis inhibitor (TAFIa). In vivo experiments indicate that selective inhibitors of TAFIa would be useful in the treatment of heart attacks. Since TAFIa rapidly degrades in solution, the homologous protein porcine pancreatic carboxypeptidase B (pp-CpB) was used in these crystallography studies. Both TAFIa and pp-CpB are zinc-based exopeptidases that are specific for basic residues. The final development candidate, BX 528, is a potent inhibitor of TAFIa (2 nM) and has almost no measurable effect on the major selectivity target, carboxypeptidase N. BX 528 was designed to mimic the tripeptide Phe-Val-Lys. A sulfonamide replaces the Phe-Val amide bond and a phosphinate connects the Val and Lys groups. The phosphinate also chelates the active-site zinc. The electrostatic interactions with the protein mimic those of the natural substrate. The primary amine in BX 528 forms a salt bridge to Asp255 at the base of the S1' pocket. The carboxylic acid interacts with Arg145 and the sulfonamide is hydrogen bonded to Arg71. Isopropyl and phenyl groups replace the side chains of Val and Phe, respectively. A series of structures are presented here that illustrate the evolution of BX 528 from thiol-based inhibitors that mimic a free C-terminal arginine. The first step in development was the replacement of the thiol with a phosphinate. This caused a precipitous drop in binding affinity. Potency was reclaimed by extending the inhibitors into the downstream binding sites for the natural substrate.


  • Organizational Affiliation

    Bayer HealthCare Pharmaceuticals, 2600 Hilltop Drive, PO Box 4099, Richmond, California 94804-0099, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carboxypeptidase B306Sus 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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
281
Query on 281

Download Ideal Coordinates CCD File 
C [auth A](2S)-2-[3-(AMINOMETHYL)PHENYL]-3-[(S)-{(1R)-1-[(2,1,3-BENZOTHIADIAZOL-4-YLSULFONYL)AMINO]-2-METHYLPROPYL}(HYDROXY)PHOSPHORYL]PROPANOIC ACID
C20 H25 N4 O6 P S2
JQWWNMPDAALMKI-HNAYVOBHSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
281 Binding MOAD:  2PJ9 IC50: 12 (nM) from 1 assay(s)
PDBBind:  2PJ9 IC50: 12 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.56 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.217 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.407α = 90
b = 78.631β = 90
c = 49.647γ = 90
Software Package:
Software NamePurpose
X-PLORmodel building
CNXrefinement
X-GENdata reduction
X-GENdata scaling
X-PLORphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-01-22
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description