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- PDB-3l33: Human mesotrypsin complexed with amyloid precursor protein inhibi... -

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Basic information

Entry
Database: PDB / ID: 3l33
TitleHuman mesotrypsin complexed with amyloid precursor protein inhibitor(APPI)
Components
  • Amyloid beta A4 protein
  • Trypsin-3
KeywordsHydrolase/Cell Adhesion / Human mesotrypsin / alzheimer's amyloid precursor protein inhibitor / APPI / Serine protease inhibitor / Hydrolase-Cell Adhesion complex
Function / homology
Function and homology information


Uptake of dietary cobalamins into enterocytes / antimicrobial humoral response / amyloid-beta complex / Alpha-defensins / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway ...Uptake of dietary cobalamins into enterocytes / antimicrobial humoral response / amyloid-beta complex / Alpha-defensins / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin / zymogen activation / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / mating behavior / regulation of spontaneous synaptic transmission / Antimicrobial peptides / 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 / 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 / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / regulation of presynapse assembly / regulation of multicellular organism growth / transition metal ion binding / intracellular copper ion homeostasis / trypsin / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / endothelial cell migration / positive regulation of T cell migration / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / forebrain development / positive regulation of chemokine production / clathrin-coated pit / digestion / 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 / serine-type peptidase activity / response to interleukin-1 / ionotropic glutamate receptor signaling pathway / positive regulation of mitotic cell cycle / cholesterol metabolic process / axonogenesis / positive regulation of calcium-mediated signaling / dendritic shaft / platelet alpha granule lumen / adult locomotory behavior / positive regulation of glycolytic process / central nervous system development / learning / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / positive regulation of long-term synaptic potentiation / endosome lumen / locomotory behavior / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / microglial cell activation / regulation of long-term neuronal synaptic plasticity / serine-type endopeptidase inhibitor activity / synapse organization / TAK1-dependent IKK and NF-kappa-B activation / positive regulation of non-canonical NF-kappaB signal transduction / neuromuscular junction / visual learning / recycling endosome / positive regulation of interleukin-6 production / Golgi lumen / cognition / neuron cellular homeostasis / positive regulation of inflammatory response
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. / 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 / : / Few Secondary Structures / Irregular / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / PH-like domain superfamily / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
FORMIC ACID / Amyloid-beta precursor protein / Trypsin-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.48 Å
AuthorsSalameh, M.A. / Soares, A.S. / Radisky, E.S.
CitationJournal: J.Biol.Chem. / Year: 2010
Title: Determinants of affinity and proteolytic stability in interactions of Kunitz family protease inhibitors with mesotrypsin.
Authors: Salameh, M.A. / Soares, A.S. / Navaneetham, D. / Sinha, D. / Walsh, P.N. / Radisky, E.S.
History
DepositionDec 16, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Trypsin-3
B: Trypsin-3
C: Trypsin-3
D: Trypsin-3
E: Amyloid beta A4 protein
F: Amyloid beta A4 protein
G: Amyloid beta A4 protein
H: Amyloid beta A4 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,34331
Polymers120,3088
Non-polymers1,03523
Water4,125229
1
A: Trypsin-3
E: Amyloid beta A4 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,53112
Polymers30,0772
Non-polymers45410
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2450 Å2
ΔGint-23 kcal/mol
Surface area12000 Å2
MethodPISA
2
B: Trypsin-3
F: Amyloid beta A4 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,3939
Polymers30,0772
Non-polymers3167
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2290 Å2
ΔGint-22 kcal/mol
Surface area12170 Å2
MethodPISA
3
C: Trypsin-3
G: Amyloid beta A4 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2556
Polymers30,0772
Non-polymers1784
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1780 Å2
ΔGint-20 kcal/mol
Surface area12090 Å2
MethodPISA
4
D: Trypsin-3
H: Amyloid beta A4 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,1634
Polymers30,0772
Non-polymers862
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1500 Å2
ΔGint-19 kcal/mol
Surface area12070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.793, 130.067, 132.338
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: Protein
Trypsin-3 / Trypsin III / Brain trypsinogen / Mesotrypsinogen / Trypsin IV / Serine protease 3 / Serine protease 4


Mass: 24257.457 Da / Num. of mol.: 4 / Fragment: Trypsin-3 / Mutation: S195A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: BL21(DE3) / Gene: PRSS3, PRSS4, TRY3, TRY4 / Production host: Escherichia coli (E. coli) / References: UniProt: P35030, trypsin
#2: Protein
Amyloid beta A4 protein / Alzheimer disease amyloid protein / ABPP / APPI / APP


Mass: 5819.501 Da / Num. of mol.: 4 / Fragment: UNP residues 290-341
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APP, A4, AD1 / Production host: Pichia pastoris (fungus) / References: UniProt: P05067
#3: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 19 / Source method: obtained synthetically / Formula: CH2O2
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 229 / 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: 3.32 Å3/Da / Density % sol: 62.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 4M sodium formate solution, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X12B
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.48→23.702 Å / Num. all: 57050 / Num. obs: 57050 / % possible obs: 99.3 % / Redundancy: 14.2 % / Rmerge(I) obs: 0.263 / Rsym value: 0.263 / Net I/σ(I): 11.1
Reflection shellResolution: 2.48→2.61 Å / Redundancy: 12.4 % / Rmerge(I) obs: 0.024 / Mean I/σ(I) obs: 0.3 / Num. measured all: 98361 / Num. unique all: 7901 / Rsym value: 0.02353 / % possible all: 95.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLM3.2.25data reduction
SCALA3.2.25data scaling
PHASER2007_05_29_2026phasing
PHENIXrefinement
PDB_EXTRACT3.005data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.48→23.702 Å / Occupancy max: 1 / Occupancy min: 0 / FOM work R set: 0.843 / Stereochemistry target values: mlhl
RfactorNum. reflection% reflection
Rfree0.256 1992 3.5 %
Rwork0.198 54882 -
obs-56874 99.08 %
Solvent computationBsol: 73.674 Å2 / ksol: 0.426 e/Å3
Displacement parametersBiso max: 222.85 Å2 / Biso mean: 44.887 Å2 / Biso min: 10.78 Å2
Baniso -1Baniso -2Baniso -3
1-7.24 Å2-0 Å2-0 Å2
2---6.667 Å20 Å2
3----0.572 Å2
Refinement stepCycle: LAST / Resolution: 2.48→23.702 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8412 0 61 229 8702
Refine LS restraints
Refine-IDTypeDev idealWeight
X-RAY DIFFRACTIONf_angle_d0.8711
X-RAY DIFFRACTIONf_bond_d0.0081
X-RAY DIFFRACTIONf_chiral_restr0.0631
X-RAY DIFFRACTIONf_dihedral_angle_d11.6661
X-RAY DIFFRACTIONf_plane_restr0.0031
X-RAY DIFFRACTIONf_nbd_refined4.0871
LS refinement shellResolution: 2.48→2.488 Å / Total num. of bins used: 110
RfactorNum. reflection% reflection
Rwork0.261 438 -
obs--82 %

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