1YPL

X-ray crystal structure of thrombin inhibited by synthetic cyanopeptide analogue RA-1008


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.195 

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Ligand Structure Quality Assessment 


This is version 1.7 of the entry. See complete history


Literature

Design and X-ray crystal structures of human thrombin with synthetic cyanopeptide-analogues.

Radau, G.Fokkens, J.

(2007) Pharmazie 62: 83-88

  • Primary Citation of Related Structures:  
    1YPL, 1YPM

  • PubMed Abstract: 

    Based on the X-ray crystals of cocrystallized cyanopeptide-trypsin and cyanopeptide-thrombin-com-plexes, a rational drug design succeeded in the establishment of suitable lead structures for the development of new potential inhibitors of thrombin. This report deals with the design and X-ray crystallography data of new synthetic, low-molecular weight cyanopeptide-analogues, RA-1008 and RA-1014, complexed with human alpha-thrombin at 1.85 A resolution. The crystal structures of the complexes reveal, by analogy with modeling studies, that the salt bridge of Asp189 to this type of synthetic thrombin inhibitors leads to an almost identically binding into the S1 specificity pocket in comparison to the complex of the natural products, whereas in the overall binding modes the P2-P4 substructures differ from those of the leads. The strongest member of the second series of described thrombin inhibitors, RA-1014, shows in the crystal complex with thrombin a slightly higher affinity towards the enzyme than RA-1008 as confirmed by inhibition tests. This result and other key informations will be helpful to design a more potent series of inhibitors.


  • Organizational Affiliation

    Institute of Pharmacy, Ernst-Moritz-Arndt-University Greifswald, Germany. radau@uni-greifswald.de


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
thrombin light chainA [auth L]27Homo sapiensMutation(s): 0 
EC: 3.4.21.5
UniProt & NIH Common Fund Data Resources
Find proteins for P00734 (Homo sapiens)
Explore P00734 
Go to UniProtKB:  P00734
PHAROS:  P00734
GTEx:  ENSG00000180210 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00734
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Thrombin heavy chainB [auth H]257Homo sapiensMutation(s): 0 
EC: 3.4.21.5
UniProt & NIH Common Fund Data Resources
Find proteins for P00734 (Homo sapiens)
Explore P00734 
Go to UniProtKB:  P00734
PHAROS:  P00734
GTEx:  ENSG00000180210 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00734
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
HirudinC [auth I]10Hirudo medicinalisMutation(s): 0 
UniProt
Find proteins for P01050 (Hirudo medicinalis)
Explore P01050 
Go to UniProtKB:  P01050
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01050
Sequence Annotations
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  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TYS
Query on TYS
C [auth I]L-PEPTIDE LINKINGC9 H11 N O6 STYR
Binding Affinity Annotations 
IDSourceBinding Affinity
RA8 Binding MOAD:  1YPL Ki: 1.06e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.195 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.131α = 90
b = 71.63β = 100.45
c = 72.198γ = 90
Software Package:
Software NamePurpose
SHELXmodel building
SHELXL-97refinement
SCALEPACKdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-01-17
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2012-06-06
    Changes: Non-polymer description
  • Version 1.4: 2012-12-12
    Changes: Other
  • Version 1.5: 2013-03-13
    Changes: Other
  • Version 1.6: 2013-11-13
    Changes: Other
  • Version 1.7: 2017-10-11
    Changes: Refinement description