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- PDB-3hxq: Crystal Structure of Von Willebrand Factor (VWF) A1 Domain in Com... -

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Basic information

Entry
Database: PDB / ID: 3hxq
TitleCrystal Structure of Von Willebrand Factor (VWF) A1 Domain in Complex with DNA Aptamer ARC1172, an Inhibitor of VWF-Platelet Binding
Components
  • Aptamer ARC1172
  • von Willebrand Factor
KeywordsBLOOD CLOTTING/BLOOD CLOTTING REGULATOR / ARC1779 / VWF / Platelet Glycoprotein Ib / Aptamer / ARC1772 / Blood coagulation / Cell adhesion / Cleavage on pair of basic residues / Disease mutation / Disulfide bond / Extracellular matrix / Glycoprotein / Hemostasis / Isopeptide bond / Secreted / von Willebrand disease / BLOOD CLOTTING-BLOOD CLOTTING REGULATOR COMPLEX
Function / homology
Function and homology information


Defective VWF binding to collagen type I / Enhanced cleavage of VWF variant by ADAMTS13 / Defective VWF cleavage by ADAMTS13 variant / Weibel-Palade body / Defective F8 binding to von Willebrand factor / Enhanced binding of GP1BA variant to VWF multimer:collagen / Defective binding of VWF variant to GPIb:IX:V / hemostasis / platelet alpha granule / Platelet Adhesion to exposed collagen ...Defective VWF binding to collagen type I / Enhanced cleavage of VWF variant by ADAMTS13 / Defective VWF cleavage by ADAMTS13 variant / Weibel-Palade body / Defective F8 binding to von Willebrand factor / Enhanced binding of GP1BA variant to VWF multimer:collagen / Defective binding of VWF variant to GPIb:IX:V / hemostasis / platelet alpha granule / Platelet Adhesion to exposed collagen / positive regulation of intracellular signal transduction / GP1b-IX-V activation signalling / p130Cas linkage to MAPK signaling for integrins / cell-substrate adhesion / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / immunoglobulin binding / GRB2:SOS provides linkage to MAPK signaling for Integrins / Integrin cell surface interactions / collagen binding / Intrinsic Pathway of Fibrin Clot Formation / Integrin signaling / extracellular matrix / platelet alpha granule lumen / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / platelet activation / response to wounding / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by BRAF and RAF1 fusions / blood coagulation / integrin binding / Platelet degranulation / protein-folding chaperone binding / collagen-containing extracellular matrix / protease binding / cell adhesion / endoplasmic reticulum / extracellular space / extracellular exosome / extracellular region / identical protein binding
Similarity search - Function
von Willebrand factor, VWA N-terminal domain / Von Willebrand factor / VWA N-terminal / C8 domain / Uncharacterised domain, cysteine-rich / C8 / von Willebrand factor, type D domain / von Willebrand factor type D domain / VWFD domain profile. / von Willebrand factor (vWF) type D domain ...von Willebrand factor, VWA N-terminal domain / Von Willebrand factor / VWA N-terminal / C8 domain / Uncharacterised domain, cysteine-rich / C8 / von Willebrand factor, type D domain / von Willebrand factor type D domain / VWFD domain profile. / von Willebrand factor (vWF) type D domain / C-terminal cystine knot signature. / von Willebrand factor (vWF) type C domain / Trypsin Inhibitor-like, cysteine rich domain / Serine protease inhibitor-like superfamily / Trypsin Inhibitor like cysteine rich domain / C-terminal cystine knot domain profile. / Cystine knot, C-terminal / C-terminal cystine knot-like domain (CTCK) / von Willebrand factor type C domain / VWFC domain signature. / VWFC domain profile. / von Willebrand factor (vWF) type C domain / VWFC domain / von Willebrand factor, type A domain / von Willebrand factor type A domain / von Willebrand factor (vWF) type A domain / VWFA domain profile. / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
DNA / DNA (> 10) / von Willebrand factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.694 Å
AuthorsHuang, R.H. / Sadler, J.E. / Fremont, D.H. / Diener, J.L. / Schaub, R.G.
Citation
Journal: Structure / Year: 2009
Title: A structural explanation for the antithrombotic activity of ARC1172, a DNA aptamer that binds von Willebrand factor domain A1.
Authors: Huang, R.H. / Fremont, D.H. / Diener, J.L. / Schaub, R.G. / Sadler, J.E.
#1: Journal: Circulation / Year: 2007
Title: First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers.
Authors: Gilbert, J.C. / DeFeo-Fraulini, T. / Hutabarat, R.M. / Horvath, C.J. / Merlino, P.G. / Marsh, H.N. / Healy, J.M. / Boufakhreddine, S. / Holohan, T.V. / Schaub, R.G.
#2: Journal: J.Thromb.Haemost. / Year: 2009
Title: Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779.
Authors: Diener, J.L. / Daniel Lagasse, H.A. / Duerschmied, D. / Merhi, Y. / Tanguay, J.F. / Hutabarat, R. / Gilbert, J. / Wagner, D.D. / Schaub, R.
History
DepositionJun 21, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 17, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 16, 2011Group: Atomic model
Revision 1.3Mar 21, 2012Group: Database references
Revision 1.4Nov 22, 2017Group: Database references / Category: pdbx_database_related / Item: _pdbx_database_related.db_id
Revision 1.5Sep 6, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: von Willebrand Factor
B: Aptamer ARC1172


Theoretical massNumber of molelcules
Total (without water)36,7742
Polymers36,7742
Non-polymers00
Water1,838102
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2110 Å2
ΔGint-2 kcal/mol
Surface area15330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)117.781, 48.512, 62.160
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-152-

HOH

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Components

#1: Protein von Willebrand Factor / vWF / von Willebrand antigen 2 / von Willebrand antigen II


Mass: 23889.627 Da / Num. of mol.: 1
Fragment: von Willebrand factor (VWF) A1 Domain (residues 1260-1468)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: P04275
#2: DNA chain Aptamer ARC1172


Mass: 12884.188 Da / Num. of mol.: 1 / Fragment: Aptamer ARC1172 / Source method: obtained synthetically
Details: ARC1172 is a DNA oligonucleotides that bind specific target molecules, identified by selection in vitro from large random sequence libraries (termed SELEX: systematic evolution of ligands by ...Details: ARC1172 is a DNA oligonucleotides that bind specific target molecules, identified by selection in vitro from large random sequence libraries (termed SELEX: systematic evolution of ligands by exponential enrichment)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 102 / Source method: isolated from a natural source / Formula: H2O
Compound detailsAUTHOR STATE THAT THE LAST RESIDUE OF THE DNA POLYMER IS AN INVERTED-DT WHICH IS NOT MODELED DUE TO ...AUTHOR STATE THAT THE LAST RESIDUE OF THE DNA POLYMER IS AN INVERTED-DT WHICH IS NOT MODELED DUE TO DISORDER. 3' INVERTED DT IS LINKED TO THE PHOSPHATE GROUP OF ITS PREVIOUS RESIDUE BY THE THIRD CARBON ATOMS OF THE SUGAR RINGS.

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.41 Å3/Da / Density % sol: 49.06 %
Crystal growTemperature: 293 K / pH: 4.6
Details: 0.2 M NH4Ac, 0.1 M NaAc, 30% PEG4000, pH 4.6, EVAPORATION, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Mar 17, 2008
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.694→38 Å / Num. obs: 9819 / % possible obs: 94.8 % / Observed criterion σ(I): 0 / Redundancy: 6.4 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 17.2
Reflection shellResolution: 2.69→2.8 Å / Redundancy: 4 % / Rmerge(I) obs: 0.316 / Mean I/σ(I) obs: 2.8 / % possible all: 83.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
PHENIX(phenix.refine)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3HXO

3hxo


Resolution: 2.694→38 Å / Occupancy max: 1 / Occupancy min: 0.47 / SU ML: 0.44 / σ(F): 1.5 / Phase error: 27.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.279 471 4.81 %
Rwork0.221 9312 -
obs0.223 9783 94.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 44.193 Å2 / ksol: 0.311 e/Å3
Displacement parametersBiso max: 170.21 Å2 / Biso mean: 63.419 Å2 / Biso min: 17.48 Å2
Refinement stepCycle: LAST / Resolution: 2.694→38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1618 833 0 102 2553
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032587
X-RAY DIFFRACTIONf_angle_d0.7253667
X-RAY DIFFRACTIONf_dihedral_angle_d22.2671044
X-RAY DIFFRACTIONf_chiral_restr0.042414
X-RAY DIFFRACTIONf_plane_restr0.002327
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.694-3.08370.35271470.29352828X-RAY DIFFRACTION89
3.0837-3.88460.25351780.21293103X-RAY DIFFRACTION96
3.8846-38.24750.26381460.19973381X-RAY DIFFRACTION98
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.9018-3.52711.35735.27540.31874.32060.53590.68510.7053-0.5113-0.6896-0.83950.29610.62480.00070.23580.18610.11630.26060.16410.130143.7633-33.384111.8842
21.6195-0.68571.84322.8935-1.43264.9929-0.1891-0.21850.12620.46170.00260.83640.0117-1.3092-0.02520.28320.25170.00360.5948-0.17650.565515.7255-16.984516.6704
3-0.0242-0.00840.0216-0.05240.03150.24510.03080.10580.0273-0.03080.03830.0298-0.02910.0567-00.29720.0096-0.01860.22260.11930.093730.1872-26.726214.2476
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain A and not (water)A0
2X-RAY DIFFRACTION2chain B and not (water)B0
3X-RAY DIFFRACTION3water0

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