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- PDB-4mvl: Crystal structure of an engineered lipocalin (Anticalin H1GA) in ... -

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Basic information

Entry
Database: PDB / ID: 4mvl
TitleCrystal structure of an engineered lipocalin (Anticalin H1GA) in complex with the Alzheimer amyloid peptide Abeta1-40
Components
  • Beta-amyloid protein 40
  • Neutrophil gelatinase-associated lipocalin
KeywordsPROTEIN BINDING/PROTEIN FIBRIL / beta-barrel / engineered lipocalin / binding protein / PROTEIN BINDING-PROTEIN FIBRIL complex
Function / homology
Function and homology information


positive regulation of iron ion import across plasma membrane / positive regulation of hippocampal neuron apoptotic process / positive regulation of endothelial tube morphogenesis / negative regulation of hippocampal neuron apoptotic process / positive regulation of cell projection organization / Metal sequestration by antimicrobial proteins / siderophore transport / response to kainic acid / response to mycotoxin / response to blue light ...positive regulation of iron ion import across plasma membrane / positive regulation of hippocampal neuron apoptotic process / positive regulation of endothelial tube morphogenesis / negative regulation of hippocampal neuron apoptotic process / positive regulation of cell projection organization / Metal sequestration by antimicrobial proteins / siderophore transport / response to kainic acid / response to mycotoxin / response to blue light / cellular response to increased oxygen levels / response to fructose / cellular response to X-ray / short-term memory / amyloid-beta complex / cellular response to interleukin-6 / microglia development / negative regulation of presynapse assembly / collateral sprouting in absence of injury / cytosolic mRNA polyadenylation / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of synapse structure or activity / axo-dendritic transport / regulation of Wnt signaling pathway / enterobactin binding / axon midline choice point recognition / astrocyte activation involved in immune response / smooth endoplasmic reticulum calcium ion homeostasis / iron ion sequestering activity / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / response to herbicide / ciliary rootlet / response to iron(II) ion / Golgi-associated vesicle / PTB domain binding / Lysosome Vesicle Biogenesis / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / suckling behavior / COPII-coated ER to Golgi transport vesicle / positive regulation of reactive oxygen species biosynthetic process / positive regulation of protein metabolic process / dendrite development / TRAF6 mediated NF-kB activation / modulation of excitatory postsynaptic potential / presynaptic active zone / Advanced glycosylation endproduct receptor signaling / signaling receptor activator activity / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / neuromuscular process controlling balance / transition metal ion binding / cellular response to interleukin-1 / regulation of multicellular organism growth / intracellular copper ion homeostasis / regulation of presynapse assembly / negative regulation of neuron differentiation / ECM proteoglycans / long-term memory / spindle midzone / positive regulation of T cell migration / forebrain development / smooth endoplasmic reticulum / cellular response to nutrient levels / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of G2/M transition of mitotic cell cycle / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / positive regulation of endothelial cell migration / ionotropic glutamate receptor signaling pathway / axonogenesis / response to interleukin-1 / cholesterol metabolic process / positive regulation of calcium-mediated signaling / positive regulation of mitotic cell cycle / protein serine/threonine kinase binding / platelet alpha granule lumen / positive regulation of glycolytic process / adult locomotory behavior / dendritic shaft / central nervous system development / positive regulation of long-term synaptic potentiation / positive regulation of interleukin-1 beta production / Iron uptake and transport / trans-Golgi network membrane / endosome lumen / acute-phase response / TAK1-dependent IKK and NF-kappa-B activation / learning
Similarity search - Function
Neutrophil gelatinase-associated lipocalin/epididymal-specific lipocalin-12 / Lipocalin / 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 ...Neutrophil gelatinase-associated lipocalin/epididymal-specific lipocalin-12 / Lipocalin / 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 / Lipocalin family conserved site / 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 / Lipocalin / cytosolic fatty-acid binding protein family / Lipocalin/cytosolic fatty-acid binding domain / Calycin beta-barrel core domain / Calycin / Lipocalin / Lipocalin signature. / PH-like domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Amyloid-beta precursor protein / Neutrophil gelatinase-associated lipocalin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsEichinger, A. / Skerra, A.
CitationJournal: Biochem.J. / Year: 2016
Title: High-affinity Anticalins with aggregation-blocking activity directed against the Alzheimer beta-amyloid peptide.
Authors: Rauth, S. / Hinz, D. / Borger, M. / Uhrig, M. / Mayhaus, M. / Riemenschneider, M. / Skerra, A.
History
DepositionSep 24, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 20, 2016Group: Database references
Revision 1.2Jun 15, 2016Group: Database references
Revision 1.3Sep 20, 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 / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.4Nov 6, 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: Neutrophil gelatinase-associated lipocalin
B: Neutrophil gelatinase-associated lipocalin
C: Neutrophil gelatinase-associated lipocalin
D: Neutrophil gelatinase-associated lipocalin
E: Beta-amyloid protein 40
F: Beta-amyloid protein 40
G: Beta-amyloid protein 40
H: Beta-amyloid protein 40


Theoretical massNumber of molelcules
Total (without water)103,1408
Polymers103,1408
Non-polymers00
Water2,324129
1
A: Neutrophil gelatinase-associated lipocalin
E: Beta-amyloid protein 40


Theoretical massNumber of molelcules
Total (without water)25,7852
Polymers25,7852
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1580 Å2
ΔGint-7 kcal/mol
Surface area10330 Å2
MethodPISA
2
B: Neutrophil gelatinase-associated lipocalin
F: Beta-amyloid protein 40


Theoretical massNumber of molelcules
Total (without water)25,7852
Polymers25,7852
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1410 Å2
ΔGint-8 kcal/mol
Surface area10250 Å2
MethodPISA
3
C: Neutrophil gelatinase-associated lipocalin
G: Beta-amyloid protein 40


Theoretical massNumber of molelcules
Total (without water)25,7852
Polymers25,7852
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1370 Å2
ΔGint-9 kcal/mol
Surface area10360 Å2
MethodPISA
4
D: Neutrophil gelatinase-associated lipocalin
H: Beta-amyloid protein 40


Theoretical massNumber of molelcules
Total (without water)25,7852
Polymers25,7852
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1340 Å2
ΔGint-9 kcal/mol
Surface area10350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.300, 79.180, 142.590
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Neutrophil gelatinase-associated lipocalin / NGAL / 25 kDa alpha-2-microglobulin-related subunit of MMP-9 / Lipocalin-2 / Oncogene 24p3 / ...NGAL / 25 kDa alpha-2-microglobulin-related subunit of MMP-9 / Lipocalin-2 / Oncogene 24p3 / Siderocalin LCN2 / p25


Mass: 21449.244 Da / Num. of mol.: 4 / Fragment: UNP residues 21-198
Mutation: Q28H,L36A,A40V,I41L,Q49L,L70G,R72D,K73D,D77L,W79K,C87S,N96R,Y100E,L103G,Y106W,K125E,S127A,Y132T,K134N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: engineered variant H1GA, HNL, LCN2, LCN2 (NGAL_HUMAN), NGAL
Plasmid: pNGAL98-H1GA / Production host: Escherichia coli (E. coli) / Strain (production host): JM83 / References: UniProt: P80188
#2: Protein/peptide
Beta-amyloid protein 40 / Beta-APP40


Mass: 4335.852 Da / Num. of mol.: 4 / Fragment: UNP residues 672-711 / Source method: obtained synthetically
Details: The Abeta(1-40) peptide was synthesized without modifications.
Source: (synth.) Homo sapiens (human) / References: UniProt: P05067
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 129 / 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 / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.17 Å3/Da / Density % sol: 43.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 24 % (w/v) PEG 3350, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 2, 2010 / Details: mirrors
RadiationMonochromator: Si 111 crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.516
11K, H, -L20.484
ReflectionResolution: 2.3→71.295 Å / Num. all: 39966 / Num. obs: 39966 / % possible obs: 98.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Redundancy: 5.9 % / Rsym value: 0.088 / Net I/σ(I): 13.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.3-2.425.50.2243.43045555380.22495.3
2.42-2.575.50.1774.32933453650.17797
2.57-2.755.50.14352834451170.14398.3
2.75-2.975.70.1066.62736748180.10698.9
2.97-3.255.80.0847.72562344500.08499.5
3.25-3.645.90.0788.12397640730.07899.5
3.64-4.26.20.0857.42262436490.08599.9
4.2-5.146.70.0847.32066330700.084100
5.14-7.2770.0648.71710824560.064100
7.27-39.656.40.0588.9922014300.05899.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.16data scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
MAR345dtbdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4GH7

4gh7


Resolution: 2.3→71.295 Å / Cor.coef. Fo:Fc: 0.878 / Cor.coef. Fo:Fc free: 0.833 / WRfactor Rfree: 0.2866 / WRfactor Rwork: 0.223 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7508 / SU B: 14.2 / SU ML: 0.172 / SU R Cruickshank DPI: 0.0719 / SU Rfree: 0.0555 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.072 / ESU R Free: 0.055 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2794 2026 5.1 %RANDOM
Rwork0.219 ---
all0.2221 39966 --
obs0.219 39844 97.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 69.09 Å2 / Biso mean: 26.1626 Å2 / Biso min: 2.25 Å2
Baniso -1Baniso -2Baniso -3
1--14.53 Å2-0 Å2-0 Å2
2---3.37 Å20 Å2
3---17.9 Å2
Refinement stepCycle: LAST / Resolution: 2.3→71.295 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5864 0 0 129 5993
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.026012
X-RAY DIFFRACTIONr_angle_refined_deg1.0241.9588142
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6365722
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.5424.602289
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.882151027
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8711528
X-RAY DIFFRACTIONr_chiral_restr0.0670.2883
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214588
LS refinement shellResolution: 2.3→2.356 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 123 -
Rwork0.208 2469 -
all-2592 -
obs--88.13 %
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)
10.8833-0.0464-0.04240.3296-0.04620.5899-0.00550.04840.0413-0.0120.0025-0.0016-0.0055-0.01690.0030.1122-0.00140.00130.08460.02080.0063-19.005721.8816-6.1139
20.69110.24860.05510.6871-0.17920.8867-0.02530.0492-0.0496-0.10130.02550.0070.07380.0054-0.00020.1657-0.00550.00510.08870.0020.0054-26.1581-9.51822.187
30.8583-0.00850.13990.69040.10320.78480.0549-0.08680.00710.0652-0.03890.08430.0243-0.0293-0.0160.157-0.01190.00040.1294-0.00530.012-30.0435-5.7567-37.1371
40.25050.0110.10151.082-0.2160.7954-0.02590.01020.0108-0.0215-0.0073-0.11320.05820.03070.03320.1342-0.0045-0.01170.08570.00220.01395.72841.6843-30.8951
50.4447-0.4222-0.98712.72110.97672.19580.04820.11880.0265-0.06460.0086-0.0504-0.1307-0.2534-0.05680.15280.0263-0.00420.13750.03420.0109-24.358928.827-8.319
61.10782.25260.94576.142-0.43544.39420.03740.1823-0.32810.0480.451-0.52640.1535-0.0018-0.48850.2443-0.00320.01750.1607-0.04140.1146-30.4839-17.66592.0946
70.45570.8321-0.31071.6771-0.61470.22620.21180.04520.26030.2591-0.0120.5906-0.101-0.0007-0.19990.25920.00990.03730.1925-0.05060.2331-35.8598-11.48-37.5246
82.53551.46470.97430.84620.5875.41280.00950.0407-0.18090.00730.0209-0.105-0.1712-0.0887-0.03040.14070.0234-0.0030.0975-0.01120.035310.5962-4.383-29.7676
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A5 - 177
2X-RAY DIFFRACTION2B6 - 177
3X-RAY DIFFRACTION3C5 - 178
4X-RAY DIFFRACTION4D7 - 177
5X-RAY DIFFRACTION5E17 - 27
6X-RAY DIFFRACTION6F17 - 27
7X-RAY DIFFRACTION7G18 - 26
8X-RAY DIFFRACTION8H18 - 26

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