6QIG

Metalloproteinase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.8 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.205 

wwPDB Validation 3D Report Full Report


This is version 1.0 of the entry. See complete history

Literature

Crystal structure and substrate-induced activation of ADAMTS13.

Petri, A.Kim, H.J.Xu, Y.de Groot, R.Li, C.Vandenbulcke, A.Vanhoorelbeke, K.Emsley, J.Crawley, J.T.B.

(2019) Nat Commun 10: 3781-3781

  • DOI: 10.1038/s41467-019-11474-5

  • PubMed Abstract: 
  • Platelet recruitment to sites of blood vessel damage is highly dependent upon von Willebrand factor (VWF). VWF platelet-tethering function is proteolytically regulated by the metalloprotease ADAMTS13. Proteolysis depends upon shear-induced conformati ...

    Platelet recruitment to sites of blood vessel damage is highly dependent upon von Willebrand factor (VWF). VWF platelet-tethering function is proteolytically regulated by the metalloprotease ADAMTS13. Proteolysis depends upon shear-induced conformational changes in VWF that reveal the A2 domain cleavage site. Multiple ADAMTS13 exosite interactions are involved in recognition of the unfolded A2 domain. Here we report through kinetic analyses that, in binding VWF, the ADAMTS13 cysteine-rich and spacer domain exosites bring enzyme and substrate into proximity. Thereafter, binding of the ADAMTS13 disintegrin-like domain exosite to VWF allosterically activates the adjacent metalloprotease domain to facilitate proteolysis. The crystal structure of the ADAMTS13 metalloprotease to spacer domains reveals that the metalloprotease domain exhibits a latent conformation in which the active-site cleft is occluded supporting the requirement for an allosteric change to enable accommodation of the substrate. Our data demonstrate that VWF functions as both the activating cofactor and substrate for ADAMTS13.


    Organizational Affiliation

    Centre for Haematology, Imperial College London, London, UK.,Laboratory for Thrombosis Research, KU Leuven, Kortrijk, Belgium.,Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK. jonas.emsley@nottingham.ac.uk.,Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK.,Centre for Haematology, Imperial College London, London, UK. j.crawley@imperial.ac.uk.




Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Antibody Light Chain
L
213N/AMutation(s): 0 
Protein Feature View is not available: No corresponding UniProt sequence found.
Entity ID: 2
MoleculeChainsSequence LengthOrganismDetails
Antibody Heavy Chain
H
227N/AMutation(s): 0 
Protein Feature View is not available: No corresponding UniProt sequence found.
Entity ID: 3
MoleculeChainsSequence LengthOrganismDetails
A disintegrin and metalloproteinase with thrombospondin motifs 13
A
604Homo sapiensMutation(s): 1 
Gene Names: ADAMTS13 (C9orf8)
EC: 3.4.24.87
Find proteins for Q76LX8 (Homo sapiens)
Go to Gene View: ADAMTS13
Go to UniProtKB:  Q76LX8
Small Molecules
Ligands 9 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
ZN
Query on ZN

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A
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
 Ligand Interaction
CL
Query on CL

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A, H, L
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
 Ligand Interaction
GOL
Query on GOL

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A, L
GLYCEROL
GLYCERIN; PROPANE-1,2,3-TRIOL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
 Ligand Interaction
CA
Query on CA

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A
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
 Ligand Interaction
MAN
Query on MAN

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A, H
ALPHA-D-MANNOSE
C6 H12 O6
WQZGKKKJIJFFOK-PQMKYFCFSA-N
 Ligand Interaction
FUC
Query on FUC

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A
ALPHA-L-FUCOSE
C6 H12 O5
SHZGCJCMOBCMKK-SXUWKVJYSA-N
 Ligand Interaction
BMA
Query on BMA

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A
BETA-D-MANNOSE
C6 H12 O6
WQZGKKKJIJFFOK-RWOPYEJCSA-N
 Ligand Interaction
PEG
Query on PEG

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A, H, L
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
 Ligand Interaction
NAG
Query on NAG

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A
N-ACETYL-D-GLUCOSAMINE
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.8 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.205 
  • Space Group: P 32 2 1
Unit Cell:
Length (Å)Angle (°)
a = 87.532α = 90.00
b = 87.532β = 90.00
c = 407.342γ = 120.00
Software Package:
Software NamePurpose
PHASERphasing
REFMACrefinement
Aimlessdata scaling
XDSdata reduction

Structure Validation

View Full Validation Report or Ramachandran Plots



Entry History & Funding Information

Deposition Data

  • Deposited Date: 2019-01-18 
  • Released Date: 2019-09-04 
  • Deposition Author(s): Kim, H.J., Emsley, J.

Funding OrganizationLocationGrant Number
British Heart FoundationUnited Kingdom--

Revision History 

  • Version 1.0: 2019-09-04
    Type: Initial release