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- PDB-6wvz: Crystal structure of anti-MET Fab arm of amivantamab in complex w... -

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Basic information

Entry
Database: PDB / ID: 6wvz
TitleCrystal structure of anti-MET Fab arm of amivantamab in complex with human MET
Components
  • Heavy Chain of anti-MET Fab of amivantamab
  • Hepatocyte growth factor receptorC-Met
  • Light Chain of anti-MET Fab of amivantamab
KeywordsTransferase/Immune System / ANTIGEN-FAB COMPLEX / SEMAPHORIN DOMAIN / PLEXIN SEMAPHORIN INTEGRIN CYSTEINE-RICH DOMAIN / ANTITUMOR PROTEIN / Transferase-Immune System complex
Function / homology
Function and homology information


hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / semaphorin receptor activity / positive regulation of endothelial cell chemotaxis ...hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / semaphorin receptor activity / positive regulation of endothelial cell chemotaxis / MET receptor recycling / pancreas development / MET activates PTPN11 / MET activates RAP1 and RAC1 / Sema4D mediated inhibition of cell attachment and migration / MET activates PI3K/AKT signaling / negative regulation of stress fiber assembly / negative regulation of Rho protein signal transduction / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of thrombin-activated receptor signaling pathway / semaphorin-plexin signaling pathway / establishment of skin barrier / MET activates RAS signaling / phagocytosis / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator activity / Negative regulation of MET activity / neuron differentiation / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / nervous system development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / cell surface receptor signaling pathway / receptor complex / phosphorylation / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular region / ATP binding / membrane / identical protein binding / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / IPT/TIG domain ...Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / IPT/TIG domain / ig-like, plexins, transcription factors / PSI domain / domain found in Plexins, Semaphorins and Integrins / IPT domain / Immunoglobulin E-set / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
FORMIC ACID / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.1 Å
AuthorsCardoso, R.M.F.
CitationJournal: J.Biol.Chem. / Year: 2021
Title: Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET.
Authors: Neijssen, J. / Cardoso, R.M.F. / Chevalier, K.M. / Wiegman, L. / Valerius, T. / Anderson, G.M. / Moores, S.L. / Schuurman, J. / Parren, P.W.H.I. / Strohl, W.R. / Chiu, M.L.
History
DepositionMay 7, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 28, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 21, 2021Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.2Oct 18, 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
H: Heavy Chain of anti-MET Fab of amivantamab
L: Light Chain of anti-MET Fab of amivantamab
M: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,9289
Polymers108,6713
Non-polymers2,2576
Water93752
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7570 Å2
ΔGint-9 kcal/mol
Surface area41660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.830, 86.830, 457.099
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

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Protein , 1 types, 1 molecules M

#3: Protein Hepatocyte growth factor receptor / C-Met / HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / ...HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / Tyrosine-protein kinase Met


Mass: 60758.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Cell line (production host): Tni Pro / Organ (production host): ovary / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P08581, receptor protein-tyrosine kinase

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Antibody , 2 types, 2 molecules HL

#1: Antibody Heavy Chain of anti-MET Fab of amivantamab


Mass: 24647.449 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Organ (production host): kidney / Production host: Homo sapiens (human)
#2: Antibody Light Chain of anti-MET Fab of amivantamab


Mass: 23264.877 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Organ (production host): kidney / Production host: Homo sapiens (human)

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Sugars , 3 types, 5 molecules

#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 53 molecules

#7: Chemical ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CH2O2
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 52 / 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: 3.96 Å3/Da / Density % sol: 68.97 % / Mosaicity: 2.699 °
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 2.5M sodium formate, 5% PEG 400, 0.1M Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 9, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.1→40.45 Å / Num. obs: 31529 / % possible obs: 94.9 % / Redundancy: 5.1 % / Rmerge(I) obs: 0.11 / Rpim(I) all: 0.049 / Rrim(I) all: 0.121 / Rsym value: 0.11 / Χ2: 0.981 / Net I/σ(I): 7.2
Reflection shellResolution: 3.1→3.15 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.431 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 1906 / CC1/2: 0.996 / Rpim(I) all: 0.024 / Rrim(I) all: 0.06 / Rsym value: 0.431 / Χ2: 0.997 / % possible all: 96.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
PHENIX1.10_2155refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1SHY and 4LEO

1shy

4leo


Resolution: 3.1→40.45 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 23.04
RfactorNum. reflection% reflectionSelection details
Rfree0.235 1592 5.07 %Random selection
Rwork0.19 ---
obs0.192 31392 94.9 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 244.1 Å2 / Biso min: 46.55 Å2
Refinement stepCycle: final / Resolution: 3.1→40.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7054 0 149 52 7255
Biso mean--169.4 74.88 -
Num. residues----946
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037410
X-RAY DIFFRACTIONf_angle_d0.87510151
X-RAY DIFFRACTIONf_dihedral_angle_d10.0414365
X-RAY DIFFRACTIONf_chiral_restr0.0571193
X-RAY DIFFRACTIONf_plane_restr0.0041293
LS refinement shellResolution: 3.1006→3.2007 Å
RfactorNum. reflection% reflection
Rfree0.3869 166 -
Rwork0.3056 --
obs--97 %
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)
14.968-3.5121-1.77493.56970.1141.24520.2439-0.61690.5059-1.07630.0914-0.5872-1.32090.4054-0.31711.32250.09-0.17910.7425-0.15480.5629-14.2907-1.4111-86.3356
25.00471.85751.91855.4653-0.19424.1220.16690.14380.5239-0.2954-0.02850.3312-1.8459-0.5318-0.08651.33570.2607-0.16920.5547-0.00850.5187-25.3642-4.0153-90.8513
33.8672-0.8241-1.29412.56620.78368.5155-0.104-0.33880.7091-0.04080.0219-0.0528-1.6841-0.0849-0.03271.62550.1396-0.18390.5939-0.03190.591-22.46374.1711-87.8574
41.43180.21711.33313.57762.43387.42080.05120.197-0.1248-0.4785-0.0635-0.1208-0.8203-0.1432-0.0761.1102-0.0142-0.15080.49-0.02570.504-20.2546-5.3535-82.9547
52.5636-1.28231.95469.5901-2.65586.44520.52520.0724-0.2379-0.8082-0.62150.11040.7699-0.10090.07941.0826-0.0193-0.14410.5992-0.07520.5379-20.6451-7.2042-53.7263
68.6577-3.29344.43982.9283-0.89293.51551.3394-0.81920.24151.0609-1.17650.9353-1.25781.1017-0.08381.343-0.2352-0.10370.764-0.04410.5441-17.9031-2.8787-45.4249
74.28580.49660.10812.9905-2.38883.94050.0953-0.1649-0.3890.3056-0.26830.15240.6598-0.32060.21311.13840.2101-0.22620.5598-0.14840.5756-27.7921-24.2265-86.7492
81.76731.8384-1.36383.1164-2.53727.13480.3147-0.2899-0.00160.3761-0.36790.2302-0.0615-0.10.06241.15650.0707-0.19260.5583-0.13260.5178-28.1189-22.3225-78.7048
97.2556-3.9292-1.53533.94124.25225.48550.3985-0.389-0.0183-0.1585-0.41040.77870.3835-0.94450.06991.0124-0.1829-0.13521.1638-0.25070.7572-35.5842-10.1616-51.3035
102.8625-0.6503-1.72138.07333.73848.58010.0789-0.5171-0.02530.4281-0.73961.3060.3401-0.7310.65421.0286-0.1916-0.13061.2707-0.220.8132-35.7026-13.4123-51.3368
110.83240.94271.80823.2131.89817.6867-0.1668-0.08910.05270.117-0.07470.1999-0.8874-0.53520.24550.90770.397-0.04970.8623-0.18050.6899-31.3356-25.3964-116.1778
125.9401-0.6018-0.36421.3054-1.40299.05040.0519-0.2881-0.2110.90260.243-0.0151-0.60960.9698-0.24280.99150.178-0.02010.6879-0.19140.5109-15.8427-30.8207-112.157
132.49460.72091.97325.95370.78296.5231-0.04960.3604-0.0330.22960.3942-0.4632-0.19481.0863-0.29650.41440.0873-0.0180.9531-0.25150.5799-9.9911-40.4334-130.1734
143.6228-0.71591.89293.61970.03395.6765-0.16510.2347-0.13920.02890.2208-0.6121-0.20451.0519-0.0250.61870.09750.01280.9578-0.29710.6514-10.8105-42.2672-132.3379
155.08973.80534.14196.57614.20236.5425-0.31610.1791-0.0666-0.27110.2730.0436-0.0021-0.2220.00690.50880.0985-0.00570.8559-0.1190.5908-39.4051-44.6643-145.0271
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1CHAIN 'H' AND (RESID 1 THROUGH 32 )H0
2X-RAY DIFFRACTION2CHAIN 'H' AND (RESID 33 THROUGH 64 )H0
3X-RAY DIFFRACTION3CHAIN 'H' AND (RESID 65 THROUGH 91 )H0
4X-RAY DIFFRACTION4CHAIN 'H' AND (RESID 92 THROUGH 125 )H0
5X-RAY DIFFRACTION5CHAIN 'H' AND (RESID 126 THROUGH 209 )H0
6X-RAY DIFFRACTION6CHAIN 'H' AND (RESID 210 THROUGH 222 )H0
7X-RAY DIFFRACTION7CHAIN 'L' AND (RESID 1 THROUGH 75 )L0
8X-RAY DIFFRACTION8CHAIN 'L' AND (RESID 76 THROUGH 113 )L0
9X-RAY DIFFRACTION9CHAIN 'L' AND (RESID 114 THROUGH 160 )L0
10X-RAY DIFFRACTION10CHAIN 'L' AND (RESID 161 THROUGH 213 )L0
11X-RAY DIFFRACTION11CHAIN 'M' AND (RESID 40 THROUGH 176 )M0
12X-RAY DIFFRACTION12CHAIN 'M' AND (RESID 177 THROUGH 233 )M0
13X-RAY DIFFRACTION13CHAIN 'M' AND (RESID 234 THROUGH 376 )M0
14X-RAY DIFFRACTION14CHAIN 'M' AND (RESID 377 THROUGH 480 )M0
15X-RAY DIFFRACTION15CHAIN 'M' AND (RESID 481 THROUGH 565 )M0

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