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- PDB-5c67: Human Mesotrypsin in complex with amyloid precursor protein inhib... -

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Basic information

Entry
Database: PDB / ID: 5c67
TitleHuman Mesotrypsin in complex with amyloid precursor protein inhibitor variant APPI-M17G/I18F/F34V
Components
  • Amyloid beta A4 protein
  • Trypsin-3
KeywordsHyrdolase/Hydrolase inhibitor / APPI / Kunitz domain / Trypsin / Hyrdolase-Hydrolase inhibitor complex
Function / homology
Function and homology information


Uptake of dietary cobalamins into enterocytes / regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / antimicrobial humoral response / microglia development / Alpha-defensins / regulation of Wnt signaling pathway / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands ...Uptake of dietary cobalamins into enterocytes / regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / antimicrobial humoral response / microglia development / Alpha-defensins / regulation of Wnt signaling pathway / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / zymogen activation / NMDA selective glutamate receptor signaling pathway / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Antimicrobial peptides / Golgi-associated vesicle / positive regulation of amyloid fibril formation / neuron remodeling / : / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / suckling behavior / nuclear envelope lumen / dendrite development / COPII-coated ER to Golgi transport vesicle / presynaptic active zone / 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 / negative regulation of long-term synaptic potentiation / regulation of multicellular organism growth / negative regulation of neuron differentiation / intracellular copper ion homeostasis / ECM proteoglycans / smooth endoplasmic reticulum / endothelial cell migration / trypsin / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / protein serine/threonine kinase binding / positive regulation of chemokine production / clathrin-coated pit / regulation of peptidyl-tyrosine phosphorylation / forebrain development / Notch signaling pathway / digestion / Mitochondrial protein degradation / neuron projection maintenance / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / serine-type peptidase activity / cholesterol metabolic process / response to interleukin-1 / positive regulation of mitotic cell cycle / adult locomotory behavior / axonogenesis / extracellular matrix organization / positive regulation of peptidyl-threonine phosphorylation / platelet alpha granule lumen / trans-Golgi network membrane / dendritic shaft / learning / positive regulation of interleukin-1 beta production / locomotory behavior / positive regulation of long-term synaptic potentiation / central nervous system development / endosome lumen / astrocyte activation / positive regulation of JNK cascade / Post-translational protein phosphorylation / synapse organization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / TAK1-dependent IKK and NF-kappa-B activation / visual learning / serine-type endopeptidase inhibitor activity / neuromuscular junction / recycling endosome / cognition / neuron cellular homeostasis / Golgi lumen / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction
Similarity search - Function
Pancreatic trypsin inhibitor Kunitz domain / Factor Xa Inhibitor / 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 ...Pancreatic trypsin inhibitor Kunitz domain / Factor Xa Inhibitor / 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 / Few Secondary Structures / Irregular / Serine proteases, trypsin family, histidine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / PH-like domain superfamily / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Amyloid-beta precursor protein / Trypsin-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsKayode, O. / Sankaran, B. / Radisky, E.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA154387 United States
CitationJournal: Biochem.J. / Year: 2016
Title: Combinatorial protein engineering of proteolytically resistant mesotrypsin inhibitors as candidates for cancer therapy.
Authors: Cohen, I. / Kayode, O. / Hockla, A. / Sankaran, B. / Radisky, D.C. / Radisky, E.S. / Papo, N.
History
DepositionJun 22, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2016Provider: repository / Type: Initial release
Revision 1.1May 18, 2016Group: Database references / Source and taxonomy
Revision 1.2Jun 1, 2016Group: Database references
Revision 1.3Sep 6, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Dec 4, 2019Group: Author supporting evidence / Derived calculations
Category: pdbx_audit_support / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.value
Revision 1.5Sep 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Trypsin-3
E: Amyloid beta A4 protein
B: Trypsin-3
C: Amyloid beta A4 protein


Theoretical massNumber of molelcules
Total (without water)66,7854
Polymers66,7854
Non-polymers00
Water1,56787
1
A: Trypsin-3
E: Amyloid beta A4 protein


Theoretical massNumber of molelcules
Total (without water)33,3922
Polymers33,3922
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint-6 kcal/mol
Surface area11990 Å2
MethodPISA
2
B: Trypsin-3
C: Amyloid beta A4 protein


Theoretical massNumber of molelcules
Total (without water)33,3922
Polymers33,3922
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1190 Å2
ΔGint-6 kcal/mol
Surface area12220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.150, 78.150, 243.730
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Trypsin-3 / Brain trypsinogen / Mesotrypsinogen / Serine protease 3 / Serine protease 4 / Trypsin III / Trypsin IV


Mass: 24257.457 Da / Num. of mol.: 2 / Mutation: S257A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRSS3, PRSS4, TRY3, TRY4 / Organ: PANCREAS / Plasmid: pTRAP-T7-wtHU3 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / Variant (production host): DE3 / References: UniProt: P35030, trypsin
#2: Protein Amyloid beta A4 protein / ABPP / APPI / APP / Alzheimer disease amyloid protein / Amyloid precursor protein / Beta-amyloid ...ABPP / APPI / APP / Alzheimer disease amyloid protein / Amyloid precursor protein / Beta-amyloid precursor protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 9134.900 Da / Num. of mol.: 2 / Mutation: M15G, I16F, F32V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APP, A4, AD1 / Plasmid: pPICZalpha-APPI / Production host: Komagataella pastoris GS115 (fungus) / Strain (production host): GS115 / References: UniProt: P05067
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.08 Å3/Da / Density % sol: 60.09 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M ammonium sulfate, 0.1 M Tris pH 7.5, and 20% PEG-1000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 28, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.83→34.6 Å / Num. obs: 66627 / % possible obs: 96.7 % / Redundancy: 6 % / Rmerge(I) obs: 0.076 / Net I/σ(I): 16.5
Reflection shellResolution: 1.83→20 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.796 / Mean I/σ(I) obs: 3.1 / % possible all: 91.1

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3L33

3l33


Resolution: 1.83→20 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.915 / SU B: 3.415 / SU ML: 0.101 / Cross valid method: THROUGHOUT / ESU R: 0.121 / ESU R Free: 0.125 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26679 974 1.4 %RANDOM
Rwork0.22324 ---
obs0.22382 66627 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.583 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å2-0 Å2-0 Å2
2---0.03 Å2-0 Å2
3---0.07 Å2
Refinement stepCycle: 1 / Resolution: 1.83→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4216 0 0 87 4303
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0194316
X-RAY DIFFRACTIONr_bond_other_d0.0010.023956
X-RAY DIFFRACTIONr_angle_refined_deg2.0081.9385874
X-RAY DIFFRACTIONr_angle_other_deg0.9263.0079075
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5095553
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.59224.628188
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.19215662
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4411519
X-RAY DIFFRACTIONr_chiral_restr0.1250.2629
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0215014
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021003
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.83→1.878 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.363 70 -
Rwork0.341 4846 -
obs--99.92 %

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