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- PDB-4xxd: Crystal Structure of mid-region amyloid beta capture by solanezumab -

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Basic information

Entry
Database: PDB / ID: 4xxd
TitleCrystal Structure of mid-region amyloid beta capture by solanezumab
Components
  • Amyloid-beta fragment
  • Fab Heavy Chain
  • Fab Light Chain
KeywordsIMMUNE SYSTEM / Fab / Amyloid-beta
Function / homology
Function and homology information


IgD immunoglobulin complex / IgA immunoglobulin complex / IgM immunoglobulin complex / IgE immunoglobulin complex / Fc-gamma receptor I complex binding / CD22 mediated BCR regulation / amyloid-beta complex / complement-dependent cytotoxicity / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation ...IgD immunoglobulin complex / IgA immunoglobulin complex / IgM immunoglobulin complex / IgE immunoglobulin complex / Fc-gamma receptor I complex binding / CD22 mediated BCR regulation / amyloid-beta complex / complement-dependent cytotoxicity / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / IgG immunoglobulin complex / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / axon midline choice point recognition / Fc epsilon receptor (FCERI) signaling / smooth endoplasmic reticulum calcium ion homeostasis / antibody-dependent cellular cytotoxicity / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / mating behavior / regulation of spontaneous synaptic transmission / immunoglobulin receptor binding / immunoglobulin complex, circulating / Classical antibody-mediated complement activation / ciliary rootlet / Golgi-associated vesicle / PTB domain binding / Lysosome Vesicle Biogenesis / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / Initial triggering of complement / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / signaling receptor activator activity / dendrite development / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / presynaptic active zone / positive regulation of protein metabolic process / neuromuscular process controlling balance / immunoglobulin mediated immune response / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / FCGR activation / regulation of presynapse assembly / regulation of multicellular organism growth / transition metal ion binding / intracellular copper ion homeostasis / negative regulation of neuron differentiation / Role of LAT2/NTAL/LAB on calcium mobilization / ECM proteoglycans / complement activation, classical pathway / Role of phospholipids in phagocytosis / spindle midzone / positive regulation of T cell migration / smooth endoplasmic reticulum / Scavenging of heme from plasma / Purinergic signaling in leishmaniasis infection / antigen binding / forebrain development / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / protein serine/threonine kinase binding / positive regulation of G2/M transition of mitotic cell cycle / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / FCERI mediated Ca+2 mobilization / response to interleukin-1 / ionotropic glutamate receptor signaling pathway / positive regulation of mitotic cell cycle / cholesterol metabolic process / FCGR3A-mediated IL10 synthesis / axonogenesis / positive regulation of calcium-mediated signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / dendritic shaft / platelet alpha granule lumen / adult locomotory behavior / positive regulation of glycolytic process / central nervous system development / Regulation of Complement cascade / learning / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / positive regulation of long-term synaptic potentiation / endosome lumen / Cell surface interactions at the vascular wall / locomotory behavior / B cell receptor signaling pathway
Similarity search - Function
Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site ...Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / PH-like domain superfamily / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Immunoglobulin kappa constant / Immunoglobulin heavy constant gamma 1 / Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.41 Å
AuthorsHermans, S.J. / Crespi, G.A.N. / Parker, M.W. / Miles, L.A.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Council Project GrantAPP1021935 Australia
CitationJournal: Sci Rep / Year: 2015
Title: Molecular basis for mid-region amyloid-beta capture by leading Alzheimer's disease immunotherapies.
Authors: Crespi, G.A. / Hermans, S.J. / Parker, M.W. / Miles, L.A.
History
DepositionJan 30, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2015Group: Database references / Structure summary
Revision 1.2Aug 23, 2017Group: Data collection / Derived calculations / Source and taxonomy
Category: diffrn_detector / diffrn_source ...diffrn_detector / diffrn_source / entity_src_gen / pdbx_entity_src_syn / pdbx_struct_oper_list
Item: _diffrn_detector.detector / _diffrn_source.pdbx_synchrotron_site ..._diffrn_detector.detector / _diffrn_source.pdbx_synchrotron_site / _entity_src_gen.pdbx_alt_source_flag / _pdbx_entity_src_syn.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Sep 27, 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
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fab Light Chain
B: Fab Heavy Chain
C: Amyloid-beta fragment
D: Fab Light Chain
E: Fab Heavy Chain
F: Amyloid-beta fragment


Theoretical massNumber of molelcules
Total (without water)99,4736
Polymers99,4736
Non-polymers00
Water5,008278
1
A: Fab Light Chain
B: Fab Heavy Chain
C: Amyloid-beta fragment


Theoretical massNumber of molelcules
Total (without water)49,7373
Polymers49,7373
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4680 Å2
ΔGint-37 kcal/mol
Surface area19690 Å2
MethodPISA
2
D: Fab Light Chain
E: Fab Heavy Chain
F: Amyloid-beta fragment


Theoretical massNumber of molelcules
Total (without water)49,7373
Polymers49,7373
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4670 Å2
ΔGint-35 kcal/mol
Surface area19650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.796, 73.555, 92.118
Angle α, β, γ (deg.)109.91, 93.64, 93.31
Int Tables number1
Space group name H-MP1

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Components

#1: Antibody Fab Light Chain


Mass: 24062.852 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pcDNA3.1+ / Cell line (production host): 292-F / Production host: Homo sapiens (human) / References: UniProt: P01834*PLUS
#2: Antibody Fab Heavy Chain


Mass: 23714.492 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pcDNA3.1+ / Cell line (production host): 293-F / Production host: Homo sapiens (human) / References: UniProt: P01857*PLUS
#3: Protein/peptide Amyloid-beta fragment


Mass: 1959.207 Da / Num. of mol.: 2 / Fragment: UNP residues 683-699 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P05067
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 278 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.57 Å3/Da / Density % sol: 52.24 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 4 / Details: PEG 3350, sodium citrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 18, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.41→46.56 Å / Num. obs: 35968 / % possible obs: 97.9 % / Redundancy: 3.9 % / Biso Wilson estimate: 43.25 Å2 / Rmerge(I) obs: 0.117 / Net I/σ(I): 8.2
Reflection shellResolution: 2.41→2.51 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.543 / Mean I/σ(I) obs: 2.3 / % possible all: 91.9

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Processing

Software
NameVersionClassification
BUSTER2.10.0refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4HIX

4hix


Resolution: 2.41→46.56 Å / Cor.coef. Fo:Fc: 0.8628 / Cor.coef. Fo:Fc free: 0.8116 / SU R Cruickshank DPI: 0.543 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.51 / SU Rfree Blow DPI: 0.298 / SU Rfree Cruickshank DPI: 0.307
RfactorNum. reflection% reflectionSelection details
Rfree0.2898 1793 4.99 %RANDOM
Rwork0.2492 ---
obs0.2512 35908 97.67 %-
Displacement parametersBiso mean: 38.44 Å2
Baniso -1Baniso -2Baniso -3
1--8.1514 Å2-1.8801 Å2-0.2616 Å2
2---2.6342 Å2-3.4584 Å2
3---10.7856 Å2
Refine analyzeLuzzati coordinate error obs: 0.445 Å
Refinement stepCycle: 1 / Resolution: 2.41→46.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6572 0 0 278 6850
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0116720HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.299140HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2214SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes139HARMONIC2
X-RAY DIFFRACTIONt_gen_planes981HARMONIC5
X-RAY DIFFRACTIONt_it6720HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.28
X-RAY DIFFRACTIONt_other_torsion19.11
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion879SEMIHARMONIC5
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_contact7293SEMIHARMONIC4
LS refinement shellResolution: 2.41→2.48 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.3285 116 4.35 %
Rwork0.2641 2552 -
all0.2668 2668 -
obs--97.67 %
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)
10.127-0.30960.01691.58980.27730.87830.13830.02470.1134-0.1872-0.00580.0207-0.0974-0.0276-0.13240.03230.0318-0.0055-0.07650.0208-0.1041-110.4889-8.376-23.7279
21.0832-0.5296-0.20511.0916-0.33571.25690.12080.01370.0029-0.0470.05560.16070.0989-0.0913-0.1764-0.10720.0189-0.0671-0.04420.0185-0.0809-112.0476-17.877-8.3922
30.8390.8194-0.19472.45290.7062.42430.1071-0.1890.11530.02520.00910.2145-0.12660.3101-0.1163-0.08880.0558-0.0287-0.00770.0001-0.2648-115.4315-29.562833.0003
41.19460.2672-0.25430.4648-0.1681.45420.0877-0.10850.074-0.0043-0.0540.02680.01310.3791-0.0337-0.13920.0536-0.02550.06560.0075-0.1621-113.9074-26.958615.0488
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|1 - A|213 }A1 - 213
2X-RAY DIFFRACTION2{ B|2 - B|208 }B2 - 208
3X-RAY DIFFRACTION3{ D|1 - D|212 }D1 - 212
4X-RAY DIFFRACTION4{ E|2 - E|209 }E2 - 209

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