4YLQ

Crystal Structure of a FVIIa-Trypsin Chimera (FT) in Complex with Soluble Tissue Factor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.174 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.141 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Molecular Basis of Enhanced Activity in Factor VIIa-Trypsin Variants Conveys Insights into Tissue Factor-mediated Allosteric Regulation of Factor VIIa Activity.

Sorensen, A.B.Madsen, J.J.Svensson, L.A.Pedersen, A.A.stergaard, H.Overgaard, M.T.Olsen, O.H.Gandhi, P.S.

(2016) J Biol Chem 291: 4671-4683

  • DOI: https://doi.org/10.1074/jbc.M115.698613
  • Primary Citation of Related Structures:  
    4YLQ, 4Z6A, 4ZMA

  • PubMed Abstract: 

    The complex of coagulation factor VIIa (FVIIa), a trypsin-like serine protease, and membrane-bound tissue factor (TF) initiates blood coagulation upon vascular injury. Binding of TF to FVIIa promotes allosteric conformational changes in the FVIIa protease domain and improves its catalytic properties. Extensive studies have revealed two putative pathways for this allosteric communication. Here we provide further details of this allosteric communication by investigating FVIIa loop swap variants containing the 170 loop of trypsin that display TF-independent enhanced activity. Using x-ray crystallography, we show that the introduced 170 loop from trypsin directly interacts with the FVIIa active site, stabilizing segment 215-217 and activation loop 3, leading to enhanced activity. Molecular dynamics simulations and novel fluorescence quenching studies support that segment 215-217 conformation is pivotal to the enhanced activity of the FVIIa variants. We speculate that the allosteric regulation of FVIIa activity by TF binding follows a similar path in conjunction with protease domain N terminus insertion, suggesting a more complete molecular basis of TF-mediated allosteric enhancement of FVIIa activity.


  • Organizational Affiliation

    From Global Research, Novo Nordisk A/S, 2760 Måløv, Denmark, Department of Chemistry and Bioscience, Aalborg University, 9220 Aalborg, Denmark, and.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor VIIA [auth L]152Homo sapiensMutation(s): 0 
Gene Names: F7
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]249Homo sapiensMutation(s): 7 
Gene Names: F7
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]219Homo sapiensMutation(s): 0 
Gene Names: F3
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
Oligosaccharides

Help

Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-xylopyranose-(1-3)-alpha-D-xylopyranose-(1-3)-beta-D-glucopyranoseD [auth A]3O-Glycosylation
Glycosylation Resources
GlyTouCan:  G41179DF
GlyCosmos:  G41179DF
GlyGen:  G41179DF
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0Z7
Query on 0Z7

Download Ideal Coordinates CCD File 
O [auth H]N-acetyl-D-phenylalanyl-N-[(2S,3S)-6-carbamimidamido-1-chloro-2-hydroxyhexan-3-yl]-L-phenylalaninamide
C27 H38 Cl N6 O4
SPENPXIFXGPVHG-UARRHKHWSA-O
FUC
Query on FUC

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

Download Ideal Coordinates CCD File 
AA [auth T]
BA [auth T]
CA [auth T]
DA [auth T]
EA [auth T]
AA [auth T],
BA [auth T],
CA [auth T],
DA [auth T],
EA [auth T],
FA [auth T],
GA [auth T],
HA [auth T],
IA [auth T],
JA [auth T],
KA [auth T],
LA [auth T],
N [auth L],
Q [auth H],
R [auth H],
S [auth H],
T [auth H],
U [auth H],
V [auth H],
X [auth H],
Y [auth H],
Z [auth H]
TETRAMETHYLAMMONIUM ION
C4 H12 N
QEMXHQIAXOOASZ-UHFFFAOYSA-N
POL
Query on POL

Download Ideal Coordinates CCD File 
W [auth H]N-PROPANOL
C3 H8 O
BDERNNFJNOPAEC-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
E [auth L]
F [auth L]
G [auth L]
H [auth L]
I [auth L]
E [auth L],
F [auth L],
G [auth L],
H [auth L],
I [auth L],
J [auth L],
K [auth L],
L,
P [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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.174 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.141 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.31α = 90
b = 80.04β = 90
c = 123.38γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-30
    Type: Initial release
  • Version 1.1: 2016-01-13
    Changes: Database references
  • Version 1.2: 2016-03-09
    Changes: Database references
  • Version 1.3: 2018-01-17
    Changes: Data collection
  • Version 1.4: 2019-10-16
    Changes: Data collection
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Source and taxonomy, Structure summary
  • Version 2.1: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary