2EC9

Crystal structure analysis of human Factor VIIa , Souluble tissue factor complexed with BCX-3607


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.242 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Probing the S2 site of factor VIIa to generate potent and selective inhibitors: the structure of BCX-3607 in complex with tissue factor-factor VIIa.

Krishnan, R.Kotian, P.L.Chand, P.Bantia, S.Rowland, S.Babu, Y.S.

(2007) Acta Crystallogr D Biol Crystallogr 63: 689-697

  • DOI: https://doi.org/10.1107/S0907444907014187
  • Primary Citation of Related Structures:  
    2EC9

  • PubMed Abstract: 

    Factor VIIa (FVIIa) is a trypsin-like serine protease in the coagulation cascade. Its complex with tissue factor (TF) triggers the extrinsic pathway of the coagulation cascade, generating a blood clot. Research programs at several centers now recognize the important roles played by TF and FVIIa in both the thrombotic and inflammatory processes associated with cardiovascular diseases. Therefore, inhibition of the TF-FVIIa complex is seen as a promising target that is key to the development of clinical candidates for various cardiovascular applications. The crystal structure of the TF-FVIIa enzyme complex has been analyzed in order to design and synthesize small-molecule inhibitors. Using structure-based drug design (SBDD), a new series of inhibitors have been discovered that demonstrate high potency against the TF-FVIIa complex while maintaining substantial selectivity versus other closely related serine proteases such as trypsin, thrombin, factor Xa and plasmin.


  • Organizational Affiliation

    BioCryst Pharmaceuticals, 2190 Parkway Lake Drive, Birmingham, AL 35216, USA. rkrishnan@biocryst.com


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor VIIA [auth L]142Homo sapiensMutation(s): 0 
EC: 3.4.21.21
UniProt & NIH Common Fund Data Resources
Find proteins for P08709 (Homo sapiens)
Explore P08709 
Go to UniProtKB:  P08709
PHAROS:  P08709
GTEx:  ENSG00000057593 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08709
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor VIIB [auth H]254Homo sapiensMutation(s): 0 
EC: 3.4.21.21
UniProt & NIH Common Fund Data Resources
Find proteins for P08709 (Homo sapiens)
Explore P08709 
Go to UniProtKB:  P08709
PHAROS:  P08709
GTEx:  ENSG00000057593 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08709
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Tissue factorC [auth T]75Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P13726 (Homo sapiens)
Explore P13726 
Go to UniProtKB:  P13726
PHAROS:  P13726
GTEx:  ENSG00000117525 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP13726
Sequence Annotations
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Tissue factorD [auth U]120Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P13726 (Homo sapiens)
Explore P13726 
Go to UniProtKB:  P13726
PHAROS:  P13726
GTEx:  ENSG00000117525 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP13726
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
24X
Query on 24X

Download Ideal Coordinates CCD File 
P [auth H]2'-((5-CARBAMIMIDOYLPYRIDIN-2-YLAMINO)METHYL)-4-(ISOBUTYLCARBAMOYL)-4'-VINYLBIPHENYL-2-CARBOXYLIC ACID
C27 H29 N5 O3
HHFWQMFTPDFWLM-UHFFFAOYSA-N
FUC
Query on FUC

Download Ideal Coordinates CCD File 
F [auth L]alpha-L-fucopyranose
C6 H12 O5
SHZGCJCMOBCMKK-SXUWKVJYSA-N
ASO
Query on ASO

Download Ideal Coordinates CCD File 
E [auth L]1,5-anhydro-D-glucitol
C6 H12 O5
MPCAJMNYNOGXPB-SLPGGIOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
G [auth L]
H [auth L]
I [auth L]
J [auth L]
K [auth L]
G [auth L],
H [auth L],
I [auth L],
J [auth L],
K [auth L],
L,
M [auth L],
N [auth L],
O [auth H]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CGU
Query on CGU
A [auth L]L-PEPTIDE LINKINGC6 H9 N O6GLU
Binding Affinity Annotations 
IDSourceBinding Affinity
24X Binding MOAD:  2EC9 IC50: 4.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.242 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.78α = 90
b = 81.41β = 90
c = 125.35γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
CNXrefinement
d*TREKdata reduction
CrystalCleardata scaling
CNXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-02-19
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.2: 2012-09-05
    Changes: Database references
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Data collection, Derived calculations, Structure summary
  • Version 1.4: 2023-10-25
    Changes: Data collection, Database references, Refinement description, Structure summary
  • Version 1.5: 2023-11-15
    Changes: Data collection