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- PDB-7eow: High-resolution structure of vWF A1 domain in complex with caplac... -

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Basic information

Entry
Database: PDB / ID: 7eow
TitleHigh-resolution structure of vWF A1 domain in complex with caplacizumab, the first nanobody-based medicine
Components
  • caplacizumab
  • von Willebrand factor
KeywordsSTRUCTURAL PROTEIN / vWF / vFW A1 / caplacizumab / nanobody
Function / homology
Function and homology information


Enhanced cleavage of VWF variant by ADAMTS13 / Defective VWF cleavage by ADAMTS13 variant / Defective VWF binding to collagen type I / 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 ...Enhanced cleavage of VWF variant by ADAMTS13 / Defective VWF cleavage by ADAMTS13 variant / Defective VWF binding to collagen type I / 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 (vWF) type A domain / VWFA domain profile. / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily
Similarity search - Domain/homology
von Willebrand factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsLee, H.T. / Heo, Y.-S.
CitationJournal: Biochem.Biophys.Res.Commun. / Year: 2021
Title: High-resolution structure of the vWF A1 domain in complex with caplacizumab, the first nanobody-based medicine for treating acquired TTP.
Authors: Lee, H.T. / Park, U.B. / Jeong, T.J. / Gu, N. / Lee, S.H. / Kim, Y. / Heo, Y.S.
History
DepositionApr 23, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 29, 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

Downloads & links

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Assembly

Deposited unit
A: von Willebrand factor
B: caplacizumab


Theoretical massNumber of molelcules
Total (without water)41,5672
Polymers41,5672
Non-polymers00
Water6,846380
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, size exclusion chromatography
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1240 Å2
ΔGint-3 kcal/mol
Surface area14740 Å2
Unit cell
Length a, b, c (Å)74.741, 74.741, 122.288
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61
Space group name HallP61
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z+1/2

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Components

#1: Protein von Willebrand factor / / vWF


Mass: 26508.443 Da / Num. of mol.: 1
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: Antibody caplacizumab


Mass: 15058.780 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 380 / Source method: isolated from a natural source / Formula: H2O

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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: 2.37 Å3/Da / Density % sol: 48.15 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 20 mM Tris-HCl pH 8 150 mM NaCl 10% glycerol 40% glycerol ethoxylate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 5C (4A) / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 3, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→27.55 Å / Num. obs: 48735 / % possible obs: 95.37 % / Redundancy: 5 % / Biso Wilson estimate: 20.22 Å2 / CC1/2: 0.996 / CC star: 0.999 / Rrim(I) all: 0.064 / Χ2: 1.539 / Net I/σ(I): 5.36
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 10.5 % / Mean I/σ(I) obs: 5.36 / Num. unique obs: 2549 / CC1/2: 0.943 / CC star: 0.985 / Rrim(I) all: 0.541 / Χ2: 0.473

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Processing

Software
NameVersionClassification
MxDCdata collection
PHENIX1.15.2_3472refinement
HKL-2000data scaling
PHENIXmodel building
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5GGS

5ggs


Resolution: 1.6→27.55 Å / SU ML: 0.1542 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.3908
RfactorNum. reflection% reflectionSelection details
Rfree0.1984 2373 4.87 %4.87%
Rwork0.1754 46362 --
obs0.1765 48735 95.37 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.81 Å2
Refinement stepCycle: LAST / Resolution: 1.6→27.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2600 0 0 380 2980
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00592648
X-RAY DIFFRACTIONf_angle_d0.80073573
X-RAY DIFFRACTIONf_chiral_restr0.0517394
X-RAY DIFFRACTIONf_plane_restr0.0049463
X-RAY DIFFRACTIONf_dihedral_angle_d3.00791617
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.630.21271780.1882773X-RAY DIFFRACTION98.53
1.63-1.670.21011460.18182847X-RAY DIFFRACTION99.73
1.67-1.70.2141510.1842841X-RAY DIFFRACTION99.57
1.7-1.750.23751370.18872852X-RAY DIFFRACTION99.63
1.75-1.790.22331400.18472833X-RAY DIFFRACTION99.87
1.79-1.850.18611330.18142849X-RAY DIFFRACTION99.8
1.85-1.910.21761110.20352105X-RAY DIFFRACTION73.5
1.91-1.980.35751220.31562459X-RAY DIFFRACTION87.11
1.98-2.050.19941470.17872859X-RAY DIFFRACTION99.9
2.05-2.150.22061300.17782868X-RAY DIFFRACTION100
2.15-2.260.20981340.21172231X-RAY DIFFRACTION78.62
2.26-2.40.21490.18292712X-RAY DIFFRACTION95.4
2.4-2.590.20991520.17812846X-RAY DIFFRACTION99.97
2.59-2.850.20561460.17932848X-RAY DIFFRACTION100
2.85-3.260.19251460.16682898X-RAY DIFFRACTION100
3.26-4.10.16881340.15762611X-RAY DIFFRACTION91.53
4.1-27.550.15651170.14272930X-RAY DIFFRACTION99.58
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)
11.63212438186-2.232544643530.3150226050812.32047413559-1.03299795550.797205185793-0.292743433176-0.3317465011960.07974179743960.3939907898470.243839610075-0.0764552845374-0.11343379616-0.0896694373110.001002221362660.3106866174570.0632438266422-0.07609816076270.2053469901190.02110864843110.243204861879-0.68237523221351.447360046765.3547968997
22.07271812927-1.19407382192-0.3395746690012.33828313424-0.08885434744851.18573382682-0.568690947182-0.799152224245-0.4035121802860.7528208885010.5325451506590.103607005674-0.056682307822-0.147831414746-0.1291273776790.4522195517110.148516033059-0.03981989477990.3193549231340.08355438416660.244035913949-0.12006248185146.060596530673.4119984981
30.57174186293-0.4432328974260.442008632032.315523409-0.7714918673591.87833694915-0.0540009465093-0.448957403944-0.536671044204-0.1172474043830.2059047630970.3599555956830.0869252979999-0.306730484369-0.1178757982870.2676358527640.0112306758892-0.03469173728510.1680705323440.0485770367640.3582591788260.41145775201335.031880395461.9088460878
41.64207155176-0.3911913205580.4088176041391.89827029903-0.2705396458391.12086287905-0.141256142635-0.023179530272-0.030435598117-0.03716976266650.0298943830835-0.419570349402-0.030801122880.229017775510.2057713859850.2877797902860.0174294821825-0.06194489327430.2331223862910.03649415511280.40321729391913.352911089239.257227760563.2857773134
52.48426228024-0.8590814645070.1351568751582.41206999117-0.3048639121561.44847154774-0.2519429947110.190463596847-0.0550765550099-0.3322911265150.0522198320805-0.246094968821-0.01400034359530.170799906650.1819106180250.271736620625-0.0092180643407-0.01720378960550.1870603202220.03989790650730.25533602963410.387057982539.452756660257.7546134396
64.35724924904-0.496656090596-0.02806117772953.292007760070.179593021394.94168206822-0.5152616457711.195980487530.331090576751-0.74543937322-0.0465458181301-0.289410477778-0.05253974152130.7708597745190.2305269963930.344064499117-0.06088921832610.06241176483810.3956396924170.09323565019860.33009960880416.951499162841.877979698654.3255437059
72.24176969351-0.733435667553-0.6472606951492.16360973592-1.182029049471.1792240183-0.5238053399470.6166488446680.227531534189-0.656212917590.282590019862-0.239925973595-0.3381316014190.1571367968310.2804651490590.320732671546-0.0948760067907-0.06773261807630.3363048292670.06470911375320.3869712701711.511360478649.307025563154.417714658
83.277091693620.1799527453421.984158844254.577800596940.9047846800434.32628957831-0.4914389044180.3183464630430.455515136551-0.46919393840.0704957061959-0.0449323777345-0.569734564770.3476655054320.3712119578480.314785074271-0.0121540584441-0.07985493936690.1912448593980.05658539457610.3601615683012.9858673087455.67913476856.2110044585
93.11613113784-1.578951742820.5948636819582.76793845601-1.206311127422.485370207840.07242936976040.245878814674-0.1994607718580.0287050796454-0.08110503758690.507574828231-0.0359227863029-0.219085029749-0.009150269696090.132229193421-0.01169802578620.02078091676010.1616635231160.01830485500430.10283119912-32.034097425270.708231833150.4057494188
101.50446904052-1.333668376690.3169040555842.47070518751-0.1456012526060.483943497305-0.385556693085-0.318615618289-0.14476913020.567042903510.4891308075970.01018592355270.129289694232-0.0964884500084-0.09803944370560.2340910265080.01819565067510.03192645820650.1568049058330.0255505758410.128694283476-28.592546800168.048413471954.9405609986
113.700217386971.16323444209-0.3371799795812.01555494522-0.2804516983692.33612760686-0.147250150241-0.0422226168846-0.493215193840.0111772195740.1180632742680.007416402108160.5918276165720.283746264433-0.1086642106170.2815145174490.005514228578040.008170864958810.1231239653150.01883820201730.228552852174-17.94378223956.534119096454.3857402805
122.506174680250.4384518485030.6797983818090.7156640632241.359078597513.04862992097-0.02778197654060.226053370395-0.0393535002559-0.117768901571-0.0210888475226-0.00305170523272-0.29928386867-0.1182865408510.03286217057270.1694882141830.01676770924760.01297456667290.1294201633320.01312185124850.119113265671-23.667438309472.221048192643.0124654693
131.63586981139-0.6023881939170.06901113193272.230734406520.3247904894050.6079984067620.02413989822960.0004877319891870.1933744908130.1841099200940.0385779332425-0.363408388215-0.05557026268830.164549585606-0.04323354733720.158108505319-0.000445266947719-0.01219305681480.130479184282-0.0005289932619980.153459535143-14.145263871472.375986693553.3473634057
142.10654492915-1.714001949010.7176151489273.636332949860.006141834226791.82847753278-0.0844591122816-0.004324414654180.34705282792-0.08650460700970.021427746809-0.263696827769-0.266024489252-0.02956206711960.0744466464890.227612532431-0.00512352868305-0.02459808550.1209511401160.01131732203720.167199978823-20.886056124177.73876653852.5668015871
152.42587666332-1.304504245390.7850707135654.94901118196-1.411394189911.58213095648-0.0605287451711-0.334263230775-0.2911284798790.2484782633350.2153721610660.4269469632120.244653181068-0.278425976296-0.1886332979990.247825305329-0.004695217529740.02838802645470.1427328007990.02482617781750.118262060856-24.658006047168.036786614458.2247536761
161.87944141521-1.32390152633-0.2536040555581.592233037320.08020181014050.33603957638-0.01639162584830.1538319570840.1584827024580.141196549507-0.0347617494653-0.161070486601-0.1556772144790.01330737296990.03224785069760.2216833962280.00726165045646-0.003608590002910.1661724172260.03244980463250.114671748257-27.981961028576.462532393546.0622661805
170.989126833619-0.6183834056430.9973167933374.06504008291-1.450516146852.351371179990.01526330551080.1083572477220.183137517658-0.119273283885-0.113881183696-0.6795422534940.1197780590680.2444147836830.09571257741270.1840126170810.01694837873730.01404904803760.188744848561-0.004502343188320.234855375514-9.5570257131363.729282064948.079092134
183.354969717750.685068301644-0.4959667725382.653685727240.1280123824041.68543101468-0.1653358943560.0977862081375-0.397453305172-0.08272147715560.0603979222654-0.416466556210.3503564021280.2252855714960.0661931720860.182650235486-0.002893737311740.001713851008930.1556168476630.0179176689360.149510076303-18.00080163463.02047528743.1836177231
193.50470175513-2.8986587707-0.05072011453968.402985464730.7330572247712.53186718407-0.04519806884950.174733900731-0.2055906870440.201800182123-0.04360647050950.90998167468-0.195957056112-0.356166017263-0.008710603208950.1652961764820.008876573613450.001771329880980.2319623370420.03904016862060.143901913711-34.941299029574.548592850745.4437269369
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 27 through 86 )
2X-RAY DIFFRACTION2chain 'A' and (resid 87 through 120 )
3X-RAY DIFFRACTION3chain 'A' and (resid 121 through 141 )
4X-RAY DIFFRACTION4chain 'A' and (resid 142 through 160 )
5X-RAY DIFFRACTION5chain 'A' and (resid 161 through 185 )
6X-RAY DIFFRACTION6chain 'A' and (resid 186 through 195 )
7X-RAY DIFFRACTION7chain 'A' and (resid 196 through 206 )
8X-RAY DIFFRACTION8chain 'A' and (resid 207 through 228 )
9X-RAY DIFFRACTION9chain 'B' and (resid 2 through 18 )
10X-RAY DIFFRACTION10chain 'B' and (resid 19 through 26 )
11X-RAY DIFFRACTION11chain 'B' and (resid 27 through 34 )
12X-RAY DIFFRACTION12chain 'B' and (resid 35 through 52 )
13X-RAY DIFFRACTION13chain 'B' and (resid 53 through 62 )
14X-RAY DIFFRACTION14chain 'B' and (resid 63 through 74 )
15X-RAY DIFFRACTION15chain 'B' and (resid 75 through 84 )
16X-RAY DIFFRACTION16chain 'B' and (resid 85 through 100 )
17X-RAY DIFFRACTION17chain 'B' and (resid 101 through 112 )
18X-RAY DIFFRACTION18chain 'B' and (resid 113 through 119 )
19X-RAY DIFFRACTION19chain 'B' and (resid 120 through 129 )

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