3HNB

Factor VIII Trp2313-His2315 segment is involved in membrane binding as shown by crystal structure of complex between factor VIII C2 domain and an inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.15 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 

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This is version 1.2 of the entry. See complete history


Literature

Trp2313-His2315 of factor VIII C2 domain is involved in membrane binding: structure of a complex between the C2 domain and an inhibitor of membrane binding.

Liu, Z.Lin, L.Yuan, C.Nicolaes, G.A.Chen, L.Meehan, E.J.Furie, B.Furie, B.Huang, M.

(2010) J Biol Chem 285: 8824-8829

  • DOI: https://doi.org/10.1074/jbc.M109.080168
  • Primary Citation of Related Structures:  
    3HNB, 3HNY, 3HOB

  • PubMed Abstract: 

    Factor VIII (FVIII) plays a critical role in blood coagulation by forming the tenase complex with factor IXa and calcium ions on a membrane surface containing negatively charged phospholipids. The tenase complex activates factor X during blood coagulation. The carboxyl-terminal C2 domain of FVIII is the main membrane-binding and von Willebrand factor-binding region of the protein. Mutations of FVIII cause hemophilia A, whereas elevation of FVIII activity is a risk factor for thromboembolic diseases. The C2 domain-membrane interaction has been proposed as a target of intervention for regulation of blood coagulation. A number of molecules that interrupt FVIII or factor V (FV) binding to cell membranes have been identified through high throughput screening or structure-based design. We report crystal structures of the FVIII C2 domain under three new crystallization conditions, and a high resolution (1.15 A) crystal structure of the FVIII C2 domain bound to a small molecular inhibitor. The latter structure shows that the inhibitor binds to the surface of an exposed beta-strand of the C2 domain, Trp(2313)-His(2315). This result indicates that the Trp(2313)-His(2315) segment is an important constituent of the membrane-binding motif and provides a model to understand the molecular mechanism of the C2 domain membrane interaction.


  • Organizational Affiliation

    State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor VIIIA [auth M]159Homo sapiensMutation(s): 0 
Gene Names: F8
UniProt & NIH Common Fund Data Resources
Find proteins for P00451 (Homo sapiens)
Explore P00451 
Go to UniProtKB:  P00451
PHAROS:  P00451
GTEx:  ENSG00000185010 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00451
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
768
Query on 768

Download Ideal Coordinates CCD File 
B [auth M](2R)-1-(2,4-dichlorophenoxy)-3-[(2E)-2-imino-3-(2-piperidin-1-ylethyl)-2,3-dihydro-1H-benzimidazol-1-yl]propan-2-ol
C23 H28 Cl2 N4 O2
QMRFKZWWZBZQKJ-MVXIZWJUSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
768 BindingDB:  3HNB IC50: 7800 (nM) from 1 assay(s)
PDBBind:  3HNB IC50: 7800 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.15 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.054α = 90
b = 55.775β = 90
c = 67.971γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-19
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description