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

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Basic information

Entry
Database: PDB / ID: 3hxo
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 / 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 / Weibel-Palade body / 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 / 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 / Weibel-Palade body / hemostasis / platelet alpha granule / Platelet Adhesion to exposed collagen / GP1b-IX-V activation signalling / p130Cas linkage to MAPK signaling for integrins / Defective F8 cleavage by thrombin / cell-substrate adhesion / Platelet Aggregation (Plug Formation) / GRB2:SOS provides linkage to MAPK signaling for Integrins / positive regulation of intracellular signal transduction / immunoglobulin binding / 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 / integrin binding / blood coagulation / 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 / Platelet degranulation / protein-folding chaperone binding / : / 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 / Von Willebrand factor-like domain / : / C8 domain / Uncharacterised domain, cysteine-rich / C8 / von Willebrand factor, type D domain / von Willebrand factor type D domain ...von Willebrand factor, VWA N-terminal domain / Von Willebrand factor / VWA N-terminal / Von Willebrand factor-like domain / : / 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 (vWF) type C domain / Trypsin Inhibitor-like, cysteine rich domain / Serine protease inhibitor-like superfamily / Trypsin Inhibitor like cysteine rich domain / von Willebrand factor type C domain / C-terminal cystine knot signature. / C-terminal cystine knot domain profile. / Cystine knot, C-terminal / C-terminal cystine knot-like domain (CTCK) / 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 / VWFA domain profile. / von Willebrand factor (vWF) type A domain / 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 / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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 1.2Mar 21, 2012Group: Database references
Revision 1.3Feb 26, 2020Group: Data collection / Category: reflns / Item: _reflns.pdbx_Rmerge_I_obs
Revision 1.4Sep 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
Revision 1.5Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
Water3,189177
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2030 Å2
ΔGint-3 kcal/mol
Surface area14950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.093, 66.354, 108.749
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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) / Gene: VWF, F8VWF / 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.: 177 / 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. THIS RESIDUE IS LINKED TO THE PHOSPHATE GROUP OF ITS PREVIOUS RESIDUE BY THE THIRD CARBON ATOMS OF THE SUGAR RINGS.
Has protein modificationY

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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: 2.56 Å3/Da / Density % sol: 51.87 %
Crystal growTemperature: 293 K / pH: 7.1
Details: 25% PEG3350, 0.16 M sodium fluoride, pH 7.1, EVAPORATION, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 0.9002
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 28, 2008
RadiationMonochromator: BENT GE(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9002 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. obs: 14563 / % possible obs: 94.9 % / Observed criterion σ(I): 0 / Redundancy: 6 % / Rmerge(I) obs: 0.064 / Net I/σ(I): 20.2
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.313 / Mean I/σ(I) obs: 2.6 / % possible all: 86.3

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Processing

Software
NameVersionClassification
APSBioCARS-developed GUIdata collection
MOLREPphasing
PHENIX(phenix.refine: 1.4_95)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1IJB

1ijb


Resolution: 2.4→24.88 Å / Occupancy max: 1 / Occupancy min: 0.23 / SU ML: 0.34 / σ(F): 1.51 / Phase error: 29.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.274 724 4.98 %
Rwork0.228 13821 -
obs0.23 14545 95.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 36.495 Å2 / ksol: 0.286 e/Å3
Displacement parametersBiso max: 179.29 Å2 / Biso mean: 65.658 Å2 / Biso min: 29.6 Å2
Refinement stepCycle: LAST / Resolution: 2.4→24.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1600 814 0 177 2591
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022632
X-RAY DIFFRACTIONf_angle_d0.7143743
X-RAY DIFFRACTIONf_dihedral_angle_d22.461070
X-RAY DIFFRACTIONf_chiral_restr0.037425
X-RAY DIFFRACTIONf_plane_restr0.003326
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4013-2.58650.37661410.3592482X-RAY DIFFRACTION88
2.5865-2.84650.3881460.32572648X-RAY DIFFRACTION93
2.8465-3.25760.26541450.25552782X-RAY DIFFRACTION96
3.2576-4.10120.24271560.19072869X-RAY DIFFRACTION99
4.1012-24.88320.23591360.19283040X-RAY DIFFRACTION99
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)
12.30980.8197-0.33945.1182-1.33642.96170.0409-0.03720.17120.078-0.01350.3596-0.2024-0.1742-00.34610.05930.01330.4082-0.06240.418518.9543-9.1193-21.9204
21.7858-0.55480.61652.27161.13442.99340.2485-0.9582-0.95310.9250.03280.06720.61580.3597-01.1495-0.00120.01480.83380.28671.020524.0695-33.5939-2.2977
3-0.2340.00870.08881.02-0.10970.7057-0.0874-0.06740.00430.0573-0.06820.1022-0.0032-0.044500.3173-0.00270.06690.604-0.00330.498921.1226-13.325-17.9163
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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