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- PDB-6vvu: Anti-Tryptase fab E104.v1 bound to tryptase -

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Basic information

Entry
Database: PDB / ID: 6vvu
TitleAnti-Tryptase fab E104.v1 bound to tryptase
Components
  • Fab E104.v1 heavy chain
  • Fab E104.v1 light chain
  • Tryptase alpha/beta-1
KeywordsHYDROLASE/IMMUNE SYSTEM / Fab / inhibitor / tryptase / IMMUNE SYSTEM / HYDROLASE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


tryptase / Activation of Matrix Metalloproteinases / extracellular matrix disassembly / serine-type peptidase activity / defense response / serine-type endopeptidase activity / proteolysis / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-0GJ / Tryptase alpha/beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsUltsch, M. / Koerber, J.T.
CitationJournal: Nat Commun / Year: 2020
Title: Bivalent antibody pliers inhibit β-tryptase by an allosteric mechanism dependent on the IgG hinge.
Authors: Henry R Maun / Rajesh Vij / Benjamin T Walters / Ashley Morando / Janet K Jackman / Ping Wu / Alberto Estevez / Xiaocheng Chen / Yvonne Franke / Michael T Lipari / Mark S Dennis / Daniel ...Authors: Henry R Maun / Rajesh Vij / Benjamin T Walters / Ashley Morando / Janet K Jackman / Ping Wu / Alberto Estevez / Xiaocheng Chen / Yvonne Franke / Michael T Lipari / Mark S Dennis / Daniel Kirchhofer / Claudio Ciferri / Kelly M Loyet / Tangsheng Yi / Charles Eigenbrot / Robert A Lazarus / James T Koerber /
Abstract: Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of allergic inflammatory responses in asthma. Antibodies generally inhibit proteases by blocking substrate ...Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of allergic inflammatory responses in asthma. Antibodies generally inhibit proteases by blocking substrate access by binding to active sites or exosites or by allosteric modulation. The bivalency of IgG antibodies can increase potency via avidity, but has never been described as essential for activity. Here we report an inhibitory anti-tryptase IgG antibody with a bivalency-driven mechanism of action. Using biochemical and structural data, we determine that four Fabs simultaneously occupy four exosites on the β-tryptase tetramer, inducing allosteric changes at the small interface. In the presence of heparin, the monovalent Fab shows essentially no inhibition, whereas the bivalent IgG fully inhibits β-tryptase activity in a hinge-dependent manner. Our results suggest a model where the bivalent IgG acts akin to molecular pliers, pulling the tetramer apart into inactive β-tryptase monomers, and may provide an alternative strategy for antibody engineering.
History
DepositionFeb 18, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 30, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 11, 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: Tryptase alpha/beta-1
B: Tryptase alpha/beta-1
D: Tryptase alpha/beta-1
C: Tryptase alpha/beta-1
E: Fab E104.v1 heavy chain
F: Fab E104.v1 light chain
G: Fab E104.v1 heavy chain
H: Fab E104.v1 heavy chain
I: Fab E104.v1 light chain
J: Fab E104.v1 heavy chain
K: Fab E104.v1 light chain
L: Fab E104.v1 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)315,23419
Polymers313,53012
Non-polymers1,7047
Water362
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.573, 168.811, 114.652
Angle α, β, γ (deg.)90.000, 109.970, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABDC

#1: Protein
Tryptase alpha/beta-1 / Tryptase-1 / Tryptase I / Tryptase alpha-1


Mass: 30549.043 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TPSAB1, TPS1, TPS2, TPSB1 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q15661, tryptase

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Antibody , 2 types, 8 molecules EGHJFIKL

#2: Antibody
Fab E104.v1 heavy chain


Mass: 24232.307 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Antibody
Fab E104.v1 light chain


Mass: 23601.156 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)

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Non-polymers , 3 types, 9 molecules

#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#5: Chemical
ChemComp-0GJ / L-alpha-glutamyl-N-{(1S)-4-{[amino(iminio)methyl]amino}-1-[(1S)-2-chloro-1-hydroxyethyl]butyl}glycinamide


Type: peptide-like / Mass: 395.862 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H28ClN6O5
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.6 Å3/Da / Density % sol: 52.66 %
Crystal growTemperature: 292 K / Method: vapor diffusion / pH: 8.5
Details: 0.1 M Tris pH 8.5, 0.2 M CaCl2, 20% PEG 4000 and 4% pentaerythritol ethoxylate

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 21, 2015 / Details: Monochromator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 3→90.83 Å / Num. obs: 62323 / % possible obs: 97.8 % / Redundancy: 3.4 % / Rsym value: 0.098 / Net I/σ(I): 11.3
Reflection shellResolution: 3→3.11 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.86 / Mean I/σ(I) obs: 1.37 / Num. unique obs: 6175 / CC1/2: 0.415 / CC star: 0.766 / Rpim(I) all: 0.582 / Χ2: 0.923 / % possible all: 97.8

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1FVD

1fvd


Resolution: 3→90.83 Å / Cor.coef. Fo:Fc: 0.901 / Cor.coef. Fo:Fc free: 0.881 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.386
RfactorNum. reflection% reflectionSelection details
Rfree0.232 1266 2.03 %RANDOM
Rwork0.187 ---
obs0.188 62323 97.3 %-
Displacement parametersBiso max: 182.93 Å2 / Biso mean: 71.49 Å2 / Biso min: 10.34 Å2
Baniso -1Baniso -2Baniso -3
1--6.8631 Å20 Å2-10.8479 Å2
2---8.0098 Å20 Å2
3---14.873 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: final / Resolution: 3→90.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms20689 0 103 2 20794
Biso mean--50.37 32.94 -
Num. residues----2702
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d6953SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes429HARMONIC2
X-RAY DIFFRACTIONt_gen_planes3111HARMONIC5
X-RAY DIFFRACTIONt_it21367HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion2793SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact23262SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d21367HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg29159HARMONIC21.19
X-RAY DIFFRACTIONt_omega_torsion3.09
X-RAY DIFFRACTIONt_other_torsion19.98
LS refinement shellResolution: 3→3.08 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.298 81 1.84 %
Rwork0.233 4313 -
all0.234 4394 -
obs--93.15 %
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)
11.1831-0.1071-0.16841.3173-0.60152.58-0.0954-0.30710.22940.3340.15990.136-0.3099-0.3495-0.0645-0.03280.07250.0574-0.0112-0.0732-0.058715.62615.870461.7338
21.91060.0174-0.40791.4895-0.43851.4266-0.15980.218-0.1796-0.3760.17110.00030.1631-0.1131-0.01120.0775-0.1296-0.0171-0.0778-0.024-0.087921.7269-22.479841.241
31.0046-0.13010.39741.7559-0.66351.4908-0.1218-0.15990.24690.2226-0.0553-0.4659-0.47740.25040.177-0.0654-0.1013-0.12830.0204-0.1663-0.004950.297816.850469.2641
42.37640.8589-0.62691.3155-0.50521.6952-0.1914-0.3784-0.56150.1075-0.002-0.53870.31720.44160.1934-0.16470.1258-0.0203-0.04810.01890.110153.9084-24.647156.1889
51.66860.5435-0.41372.14030.88352.1307-0.16160.3954-0.1025-0.20450.347-0.04380.0001-0.0214-0.1853-0.0974-0.0518-0.0018-0.0413-0.0421-0.032623.295221.406323.974
61.85441.8722-1.27474.1568-2.41631.2906-0.31280.11330.137-0.44980.1758-0.03940.15940.3770.1369-0.2611-0.12430.0204-0.0125-0.1029-0.002668.31040.333129.6337
72.16111.094-0.1843.5843-1.50312.89040.0527-0.2108-0.14840.3701-0.20330.0669-0.35450.38460.1506-0.21180.039-0.07550.051-0.1249-0.171745.2022-8.346898.7484
81.3192-1.6376-0.43643.126-0.6273.596-0.0052-0.2571-0.06950.42490.40310.4243-0.2113-0.6524-0.3979-0.17310.09090.1107-0.02220.1947-0.06815.0662-26.80976.0542
93.33761.0494-1.44651.97151.62443.41820.30940.2229-0.0638-0.52120.0286-0.1594-0.3384-0.0299-0.33790.1229-0.09090.175-0.0109-0.1947-0.233237.195516.5462-6.9071
103.42612.1692-0.93313.1515-0.89912.8883-0.25830.10360.4693-0.37990.49040.4410.1582-0.0681-0.2321-0.277-0.1947-0.1363-0.17050.09090.242670.568630.144712.9132
113.9507-0.8035-0.92995.8589-1.8493.11860.1395-0.5745-0.53110.4792-0.10840.21780.17430.2106-0.031-0.10510.1187-0.1084-0.07890.1184-0.215135.6871-37.6428113.6306
120.35140.0961-1.93053.55281.66587.964-0.2782-0.22830.28520.62830.2814-0.13560.55380.1314-0.0032-0.02460.07730.0181-0.1313-0.0868-0.2483-3.8465-22.6777109.61
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|16 - A|244}A16 - 244
2X-RAY DIFFRACTION1{A|302 - A|302}A302
3X-RAY DIFFRACTION2{B|16 - B|245}B16 - 245
4X-RAY DIFFRACTION2{B|302 - B|302}B302
5X-RAY DIFFRACTION3{D|16 - D|243}D16 - 243
6X-RAY DIFFRACTION3{D|302 - D|302}D302
7X-RAY DIFFRACTION4{C|16 - C|243}C16 - 243
8X-RAY DIFFRACTION4{C|301 - C|301}C301
9X-RAY DIFFRACTION5{L|2 - L|112}L2 - 112
10X-RAY DIFFRACTION5{H|2 - H|124}H2 - 124
11X-RAY DIFFRACTION6{F|1 - F|112}F1 - 112
12X-RAY DIFFRACTION6{E|2 - E|124}E2 - 124
13X-RAY DIFFRACTION7{I|1 - I|112}I1 - 112
14X-RAY DIFFRACTION7{G|1 - G|124}G1 - 124
15X-RAY DIFFRACTION8{K|2 - K|112}K2 - 112
16X-RAY DIFFRACTION8{J|2 - J|124}J2 - 124
17X-RAY DIFFRACTION9{L|113 - L|213}L113 - 213
18X-RAY DIFFRACTION9{H|133 - H|213}H133 - 213
19X-RAY DIFFRACTION10{F|113 - F|213}F113 - 213
20X-RAY DIFFRACTION10{E|133 - E|213}E133 - 213
21X-RAY DIFFRACTION11{I|113 - I|213}I113 - 213
22X-RAY DIFFRACTION11{G|133 - G|213}G133 - 213
23X-RAY DIFFRACTION12{K|113 - K|214}K113 - 214
24X-RAY DIFFRACTION12{J|133 - J|216}J133 - 216

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