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- PDB-8r38: BIIG2 anti-integrin Fab -

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Basic information

Entry
Database: PDB / ID: 8r38
TitleBIIG2 anti-integrin Fab
Components
  • BIIG2 Fab, heavy chain
  • BIIG2 Fab, light chain
KeywordsIMMUNE SYSTEM / BIIG2 Fab / anti-integrin / glycosylated
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.38 Å
AuthorsCordara, G. / Heim, J.B. / Johannesen, H. / Krengel, U.
Funding support United States, Norway, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P30 CA015704-40 United States
Norwegian Research Council245828 Norway
CitationJournal: bioRxiv / Year: 2025
Title: Shared ligand-blocking mechanism but distinct conformational modulation by α5-targeting antibodies BIIG2 and MINT1526A.
Authors: Adam Nguyen / Joel B Heim / Gabriele Cordara / Matthew C Chan / Hedda Johannesen / Cristine Charlesworth / Ming Li / Caleigh M Azumaya / Benjamin Madden / Ute Krengel / Alexander Meves / Melody G Campbell /
Abstract: Integrins are heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1 is a key mediator of angiogenesis and its dysregulation is associated with tumor progression and ...Integrins are heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1 is a key mediator of angiogenesis and its dysregulation is associated with tumor progression and metastasis. Despite numerous efforts, α5β1-targeting therapeutics have been unsuccessful due to poor efficacy and off-target effects. A contributing factor is our limited understanding of how integrin conformation influences interactions with therapeutics. Using cell-based functional assays, patient derived xenografts, biophysics, and electron microscopy, we shed light on these relationships by characterizing two anti-α5β1 antibodies, BIIG2 and MINT1526A. We show that both antibodies bind α5β1 with nanomolar affinity, reduce angiogenesis , and bind overlapping epitopes that block fibronectin binding. However, using cryoEM, we reveal that while BIIG2 binding doesn't alter the conformational states, MINT1526A restricts α5β1's range of flexibility. These insights can guide which aspects to prioritize and improve the design of future integrin-targeted therapeutics.
History
DepositionNov 8, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 25, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _pdbx_entry_details.has_protein_modification
Revision 1.2Oct 22, 2025Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: BIIG2 Fab, heavy chain
L: BIIG2 Fab, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,4639
Polymers47,2192
Non-polymers1,2457
Water4,035224
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6030 Å2
ΔGint-19 kcal/mol
Surface area19980 Å2
Unit cell
Length a, b, c (Å)62.930, 80.882, 87.469
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Antibody , 2 types, 2 molecules HL

#1: Antibody BIIG2 Fab, heavy chain


Mass: 23740.486 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-terminal glutamine modified to a pyroglutamate proline 100C (Kabat numbering) modified to 5-hydroxyproline
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Production host: Homo sapiens (human)
#2: Antibody BIIG2 Fab, light chain


Mass: 23478.137 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: lysine 199 modified to methyllysine / Source: (gene. exp.) Rattus norvegicus (Norway rat) / Production host: Homo sapiens (human)

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Sugars , 1 types, 1 molecules

#3: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE

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Non-polymers , 3 types, 230 molecules

#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
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: 2.4 Å3/Da / Density % sol: 48.8 % / Description: prism
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: crystallization solution: of 20% w/v PEG 3350, 0.2 M sodium chloride, 2.5% v/v DMSO protein buffer solution: 25 mM Bis-Tris-HCl, approx. 130 mM NaCl at pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.95372 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 28, 2019 / Details: Kirkpatrick-Baez (KB) mirror pair (VFM, HFM)
RadiationMonochromator: Si(111) double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95372 Å / Relative weight: 1
ReflectionResolution: 1.4→43.7 Å / Num. obs: 169111 / % possible obs: 99.6 % / Redundancy: 6.6 % / Biso Wilson estimate: 21.3 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.039 / Rrim(I) all: 0.104 / Net I/σ(I): 7.6
Reflection shellResolution: 1.4→1.43 Å / Redundancy: 4.5 % / Rmerge(I) obs: 2.875 / Mean I/σ(I) obs: 0.23 / Num. unique obs: 8404 / CC1/2: 0.104 / Rpim(I) all: 1.507 / Rrim(I) all: 3.266 / % possible all: 96.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0415refinement
DIALS2.2.11-gad03a188bdata reduction
Aimless0.7.9data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.38→59.38 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.961 / SU B: 1.361 / SU ML: 0.051 / Cross valid method: THROUGHOUT / ESU R: 0.067 / ESU R Free: 0.067 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2171 4717 5.1 %RANDOM
Rwork0.19537 ---
obs0.19651 86974 99.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.18 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å2-0 Å20 Å2
2--0.11 Å2-0 Å2
3---0.11 Å2
Refinement stepCycle: 1 / Resolution: 1.38→59.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3285 0 81 224 3590
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0124079
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163712
X-RAY DIFFRACTIONr_angle_refined_deg1.7031.6685595
X-RAY DIFFRACTIONr_angle_other_deg0.6191.5778670
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6865542
X-RAY DIFFRACTIONr_dihedral_angle_2_deg10.166521
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.08910675
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.080.2640
X-RAY DIFFRACTIONr_gen_planes_refined0.010.024900
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02892
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.2972.4132070
X-RAY DIFFRACTIONr_mcbond_other2.2942.4132069
X-RAY DIFFRACTIONr_mcangle_it3.3054.3372644
X-RAY DIFFRACTIONr_mcangle_other3.3054.3382645
X-RAY DIFFRACTIONr_scbond_it2.8882.6542009
X-RAY DIFFRACTIONr_scbond_other2.8872.6542010
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.2114.7582952
X-RAY DIFFRACTIONr_long_range_B_refined5.58426.214158
X-RAY DIFFRACTIONr_long_range_B_other5.56426.14131
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.38→1.416 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 345 -
Rwork0.368 5948 -
obs--93.26 %

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