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- PDB-5lv0: Structure of Human Neurolysin (E475Q) in complex with amyloid-bet... -

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Basic information

Entry
Database: PDB / ID: 5lv0
TitleStructure of Human Neurolysin (E475Q) in complex with amyloid-beta 35-40 peptide product
Components
  • GLY-VAL-VAL amyloid 35-40 fragment
  • Neurolysin, mitochondrial
KeywordsHYDROLASE / PROTEASE / MITOCHONDRIA / amyloid-beta
Function / homology
Function and homology information


neurolysin / regulation of skeletal muscle fiber differentiation / peptide metabolic process / regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands ...neurolysin / regulation of skeletal muscle fiber differentiation / peptide metabolic process / regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of Wnt signaling pathway / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / positive regulation of amyloid fibril formation / neuron remodeling / regulation of gluconeogenesis / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / protein serine/threonine kinase binding / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / : / nuclear envelope lumen / suckling behavior / presynaptic active zone / dendrite development / COPII-coated ER to Golgi transport vesicle / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / regulation of presynapse assembly / transition metal ion binding / regulation of multicellular organism growth / intracellular copper ion homeostasis / negative regulation of long-term synaptic potentiation / negative regulation of neuron differentiation / ECM proteoglycans / smooth endoplasmic reticulum / Mitochondrial protein degradation / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / clathrin-coated pit / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / forebrain development / Notch signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / neuron projection maintenance / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / cholesterol metabolic process / response to interleukin-1 / positive regulation of mitotic cell cycle / extracellular matrix organization / Peptide ligand-binding receptors / axonogenesis / adult locomotory behavior / trans-Golgi network membrane / platelet alpha granule lumen / locomotory behavior / positive regulation of peptidyl-threonine phosphorylation / dendritic shaft / learning / positive regulation of interleukin-1 beta production / central nervous system development / positive regulation of long-term synaptic potentiation / endosome lumen / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / peptide binding / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / TAK1-dependent IKK and NF-kappa-B activation / visual learning / serine-type endopeptidase inhibitor activity / neuromuscular junction / mitochondrial intermembrane space / recycling endosome / metalloendopeptidase activity / cognition / positive regulation of inflammatory response / Golgi lumen / neuron cellular homeostasis / endocytosis / positive regulation of non-canonical NF-kappaB signal transduction
Similarity search - Function
Neurolysin, domain 3 / Endopeptidase. Chain P; domain 1 / Neurolysin/Thimet oligopeptidase, N-terminal / Neurolysin/Thimet oligopeptidase, domain 2 / Peptidase M3A/M3B catalytic domain / Peptidase M3A/M3B / Peptidase family M3 / Neurolysin; domain 3 / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site ...Neurolysin, domain 3 / Endopeptidase. Chain P; domain 1 / Neurolysin/Thimet oligopeptidase, N-terminal / Neurolysin/Thimet oligopeptidase, domain 2 / Peptidase M3A/M3B catalytic domain / Peptidase M3A/M3B / Peptidase family M3 / Neurolysin; domain 3 / 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. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / 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 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 / Collagenase (Catalytic Domain) / Collagenase (Catalytic Domain) / Glutathione S-transferase Yfyf (Class Pi); Chain A, domain 2 / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / PH-like domain superfamily / Up-down Bundle / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Amyloid-beta precursor protein / Neurolysin, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsMasuyer, G. / Berntsson, R.P.-A. / Teixeira, P.F. / Kmiec, B. / Glaser, E. / Stenmark, P.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Swedish Research Council2014-5667 Sweden
CitationJournal: To Be Published
Title: Structural and functional analysis of Neurolysin, a new component of the mitochondrial peptidolytic network
Authors: Teixeira, P.F. / Masuyer, G. / Pinho, C. / Branca, R.M.M. / Kmiec, B. / Wallin, C. / Warmlander, S. / Berntsson, R.P.-A. / Ankarcrona, M. / Graslund, A. / Lehtio, J. / Stenmark, P. / Glaser, E.
History
DepositionSep 12, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 6, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2018Group: Database references / Structure summary / Category: audit_author / citation_author / Item: _audit_author.name / _citation_author.name
Revision 1.2Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Neurolysin, mitochondrial
B: Neurolysin, mitochondrial
C: GLY-VAL-VAL amyloid 35-40 fragment
D: GLY-VAL-VAL amyloid 35-40 fragment
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,6138
Polymers158,4114
Non-polymers2024
Water1,06359
1
A: Neurolysin, mitochondrial
C: GLY-VAL-VAL amyloid 35-40 fragment
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,3064
Polymers79,2052
Non-polymers1012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area910 Å2
ΔGint-51 kcal/mol
Surface area27790 Å2
MethodPISA
2
B: Neurolysin, mitochondrial
D: GLY-VAL-VAL amyloid 35-40 fragment
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,3064
Polymers79,2052
Non-polymers1012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-51 kcal/mol
Surface area27350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)131.341, 131.341, 195.979
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Neurolysin, mitochondrial / / Angiotensin-binding protein / Microsomal endopeptidase / MEP / Mitochondrial oligopeptidase M / ...Angiotensin-binding protein / Microsomal endopeptidase / MEP / Mitochondrial oligopeptidase M / Neurotensin endopeptidase


Mass: 78644.781 Da / Num. of mol.: 2 / Mutation: E475Q
Source method: isolated from a genetically manipulated source
Details: Catalytically impaired Human neurolysin / Source: (gene. exp.) Homo sapiens (human) / Gene: NLN, AGTBP, KIAA1226 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta 2 / References: UniProt: Q9BYT8, neurolysin
#2: Protein/peptide GLY-VAL-VAL amyloid 35-40 fragment


Mass: 560.707 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P05067*PLUS
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 59 / 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: 2.7 Å3/Da / Density % sol: 54.7 % / Description: elongated pyramidal shapes
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M Bis-Tris-propane, 11% PEG 3350, 10% glycerol, 0.2M potassium thiocyanate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 2, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.7→109.11 Å / Num. obs: 47196 / % possible obs: 99.2 % / Redundancy: 8.1 % / CC1/2: 0.985 / Rmerge(I) obs: 0.093 / Net I/σ(I): 13.7
Reflection shellResolution: 2.7→2.79 Å / Redundancy: 8.4 % / Rmerge(I) obs: 0.6 / Mean I/σ(I) obs: 3.2 / CC1/2: 0.595 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
iMOSFLMdata reduction
Aimless0.5.15data scaling
PHASER2.5.7phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1I1I

1i1i


Resolution: 2.7→109.11 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.914 / SU B: 32.757 / SU ML: 0.303 / Cross valid method: THROUGHOUT / ESU R: 1.456 / ESU R Free: 0.352 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26049 2329 4.9 %RANDOM
Rwork0.20958 ---
obs0.21203 44843 98.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 66.215 Å2
Baniso -1Baniso -2Baniso -3
1--1.2 Å20 Å20 Å2
2---1.2 Å20 Å2
3---2.4 Å2
Refinement stepCycle: LAST / Resolution: 2.7→109.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10723 0 4 59 10786
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01910940
X-RAY DIFFRACTIONr_bond_other_d0.0010.0210412
X-RAY DIFFRACTIONr_angle_refined_deg1.1021.96814761
X-RAY DIFFRACTIONr_angle_other_deg0.876324010
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.36851330
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.68824.33522
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.548152002
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4481566
X-RAY DIFFRACTIONr_chiral_restr0.060.21621
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212277
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022493
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_it0.8985.7695335
X-RAY DIFFRACTIONr_mcbond_other0.8985.7685334
X-RAY DIFFRACTIONr_mcangle_it1.6448.6486660
X-RAY DIFFRACTIONr_mcangle_other1.6448.6486661
X-RAY DIFFRACTIONr_scbond_it0.645.8325605
X-RAY DIFFRACTIONr_scbond_other0.645.8325605
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.2148.728101
X-RAY DIFFRACTIONr_long_range_B_refined2.78165.97512027
X-RAY DIFFRACTIONr_long_range_B_other2.77165.97212025
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.354 165 -
Rwork0.319 3299 -
obs--99.37 %
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)
10.3350.33490.18180.68320.28260.6816-0.02330.0297-0.1040.12260.0484-0.0782-0.0516-0.0805-0.02510.09130.0390.01160.037-0.01360.03562.5111-17.730720.5947
21.1706-0.1868-0.5590.36840.2550.50330.03810.1215-0.00680.0079-0.03950.07540.0074-0.00610.00140.00420.0099-0.00040.0425-0.02840.041518.588-48.9304-21.3614
30000000000000000.0659000.065900.0659000
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A15 - 680
2X-RAY DIFFRACTION2B14 - 680

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