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- PDB-5opy: Crystal structure of anti-alphaVbeta3 integrin Fab LM609 -

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Basic information

Entry
Database: PDB / ID: 5opy
TitleCrystal structure of anti-alphaVbeta3 integrin Fab LM609
Components
  • Heavy chain of LM609 Fab (antigen-binding fragment)
  • Light chain of LM609 Fab (antigen-binding fragment)
KeywordsIMMUNE SYSTEM / Antigen-binding fragment / Fab / LM609
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsBackovic, M. / Veesler, D. / Borst, A.J. / James, Z.M. / Zagotta, W. / Ginsberg, M. / Rey, F.A. / DiMaio, F.
Funding support France, United States, 3items
OrganizationGrant numberCountry
Institut PasteurRecurrent funding France
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM120553 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM008268 United States
CitationJournal: Structure / Year: 2017
Title: The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αβ Integrin via Steric Hindrance.
Authors: Andrew J Borst / Zachary M James / William N Zagotta / Mark Ginsberg / Felix A Rey / Frank DiMaio / Marija Backovic / David Veesler /
Abstract: The LM609 antibody specifically recognizes αβ integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II ...The LM609 antibody specifically recognizes αβ integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for αβ-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of αβ integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for αβ. Using single-particle electron microscopy, we show that LM609 binds at the interface between the β-propeller domain of the α chain and the βI domain of the β chain, near the RGD-binding site, of all observed integrin conformational states. Integrating these data with fluorescence size-exclusion chromatography, we demonstrate that LM609 sterically hinders access of large ligands to the RGD-binding pocket, without obstructing it. This work provides a structural framework to expedite future efforts utilizing LM609 as a diagnostic or therapeutic tool.
History
DepositionAug 10, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 25, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 30, 2022Group: Author supporting evidence / Database references / Category: database_2 / pdbx_audit_support
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization
Revision 1.3Jan 17, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
H: Heavy chain of LM609 Fab (antigen-binding fragment)
L: Light chain of LM609 Fab (antigen-binding fragment)


Theoretical massNumber of molelcules
Total (without water)50,8522
Polymers50,8522
Non-polymers00
Water3,045169
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3550 Å2
ΔGint-26 kcal/mol
Surface area18990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.810, 82.350, 92.170
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

#1: Antibody Heavy chain of LM609 Fab (antigen-binding fragment)


Mass: 27223.100 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell: Hybrydoma / Cell line (production host): Schneider S2 / Production host: Drosophila melanogaster (fruit fly)
#2: Antibody Light chain of LM609 Fab (antigen-binding fragment)


Mass: 23628.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell: Hybrydoma / Cell line (production host): Schneider S2 / Production host: Drosophila melanogaster (fruit fly)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 169 / 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: 1.97 Å3/Da / Density % sol: 37.48 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1M HEPES pH 7.5, 30% PEG 4,000 and 0.2M CaCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9801 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Sep 18, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 2.26→45.16 Å / Num. obs: 19133 / % possible obs: 99.8 % / Redundancy: 5.3 % / Biso Wilson estimate: 39.82 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.088 / Net I/σ(I): 12.7
Reflection shellResolution: 2.26→2.36 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.496 / Mean I/σ(I) obs: 3.3 / Num. unique obs: 9085 / CC1/2: 0.759 / % possible all: 98.7

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ADG

2adg


Resolution: 2.26→45.16 Å / Cor.coef. Fo:Fc: 0.9313 / Cor.coef. Fo:Fc free: 0.8944 / SU R Cruickshank DPI: 0.383 / Cross valid method: FREE R-VALUE / σ(F): 0 / SU R Blow DPI: 0.425 / SU Rfree Blow DPI: 0.247 / SU Rfree Cruickshank DPI: 0.244
RfactorNum. reflection% reflectionSelection details
Rfree0.255 954 5 %RANDOM
Rwork0.2126 ---
obs0.2147 19063 99.79 %-
Displacement parametersBiso mean: 35.44 Å2
Baniso -1Baniso -2Baniso -3
1-3.1155 Å20 Å20 Å2
2---2.2473 Å20 Å2
3----0.8682 Å2
Refine analyzeLuzzati coordinate error obs: 0.324 Å
Refinement stepCycle: 1 / Resolution: 2.26→45.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3255 0 0 169 3424
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013339HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.254546HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1098SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes68HARMONIC2
X-RAY DIFFRACTIONt_gen_planes487HARMONIC5
X-RAY DIFFRACTIONt_it3339HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.32
X-RAY DIFFRACTIONt_other_torsion19.89
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion447SEMIHARMONIC5
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_contact3798SEMIHARMONIC4
LS refinement shellResolution: 2.26→2.38 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2922 136 4.99 %
Rwork0.2666 2589 -
all0.268 2725 -
obs--99.78 %

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