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- PDB-4ci9: Crystal structure of cathepsin A, apo-structure -

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Basic information

Entry
Database: PDB / ID: 4ci9
TitleCrystal structure of cathepsin A, apo-structure
ComponentsLYSOSOMAL PROTECTIVE PROTEIN
KeywordsHYDROLASE / DRUG DISCOVERY / SERINE CARBOXYPEPTIDASE / CARDIOVASCULAR DRUG / HEART FAILURE / ENDOTHELIN / TETRAHEDRAL INTERMEDIATE / COVALENT INHIBITOR
Function / homology
Function and homology information


carboxypeptidase C / Defective NEU1 causes sialidosis / serine-type carboxypeptidase activity / Sialic acid metabolism / regulation of chaperone-mediated autophagy / Glycosphingolipid catabolism / negative regulation of chaperone-mediated autophagy / carboxypeptidase activity / MHC class II antigen presentation / lysosomal lumen ...carboxypeptidase C / Defective NEU1 causes sialidosis / serine-type carboxypeptidase activity / Sialic acid metabolism / regulation of chaperone-mediated autophagy / Glycosphingolipid catabolism / negative regulation of chaperone-mediated autophagy / carboxypeptidase activity / MHC class II antigen presentation / lysosomal lumen / enzyme activator activity / intracellular protein transport / regulation of protein stability / azurophil granule lumen / lysosome / intracellular membrane-bounded organelle / Neutrophil degranulation / endoplasmic reticulum / proteolysis / extracellular exosome / extracellular region / membrane
Similarity search - Function
Serine carboxypeptidase, serine active site / Serine carboxypeptidases, serine active site. / Peptidase S10, serine carboxypeptidase / Serine carboxypeptidases, histidine active site / Serine carboxypeptidase / Serine carboxypeptidases, histidine active site. / Alpha/Beta hydrolase fold, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / Lysosomal protective protein
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.58 Å
AuthorsSchreuder, H.A. / Liesum, A. / Kroll, K. / Boehnisch, B. / Buning, C. / Ruf, S. / Buning, C. / Sadowski, T.
Citation
Journal: Biochem. Biophys. Res. Commun. / Year: 2014
Title: Crystal structure of cathepsin A, a novel target for the treatment of cardiovascular diseases.
Authors: Schreuder, H.A. / Liesum, A. / Kroll, K. / Bohnisch, B. / Buning, C. / Ruf, S. / Sadowski, T.
#1: Journal: J.Med.Chem. / Year: 2012
Title: Novel Beta-Amino Acid Derivatives as Inhibitors of Cathepsin A.
Authors: Ruf, S. / Buning, C. / Schreuder, H. / Horstick, G. / Linz, W. / Olpp, T. / Pernerstorfer, J. / Hiss, K. / Kroll, K. / Kannt, A. / Kohlmann, M. / Linz, D. / Hubschle, T. / Rutten, H. / ...Authors: Ruf, S. / Buning, C. / Schreuder, H. / Horstick, G. / Linz, W. / Olpp, T. / Pernerstorfer, J. / Hiss, K. / Kroll, K. / Kannt, A. / Kohlmann, M. / Linz, D. / Hubschle, T. / Rutten, H. / Wirth, K. / Schmidt, T. / Sadowski, T.
History
DepositionDec 6, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 26, 2014Provider: repository / Type: Initial release
Revision 1.1Apr 2, 2014Group: Database references
Revision 1.2Mar 13, 2019Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Experimental preparation / Other
Category: citation / citation_author ...citation / citation_author / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_biol / struct_conn
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name / _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval / _struct_conn.pdbx_leaving_atom_flag
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Other / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_database_status / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_special_symmetry / pdbx_unobs_or_zero_occ_atoms / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.occupancy / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.src_method / _entity.type / _pdbx_database_status.status_code_sf / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_special_symmetry.label_asym_id / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: LYSOSOMAL PROTECTIVE PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,1559
Polymers51,8291
Non-polymers1,3258
Water11,061614
1
A: LYSOSOMAL PROTECTIVE PROTEIN
hetero molecules

A: LYSOSOMAL PROTECTIVE PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,30918
Polymers103,6592
Non-polymers2,65116
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,y,-z1
Buried area8430 Å2
ΔGint-28.5 kcal/mol
Surface area33550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.310, 102.030, 48.550
Angle α, β, γ (deg.)90.00, 101.27, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-2130-

HOH

21A-2350-

HOH

31A-2385-

HOH

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Components

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Protein / Sugars , 2 types, 3 molecules A

#1: Protein LYSOSOMAL PROTECTIVE PROTEIN / CARBOXYPEPTIDASE C / CARBOXYPEPTIDASE L / CATHEPSIN A / PROTECTIVE PROTEIN CATHEPSIN A / PPCA / ...CARBOXYPEPTIDASE C / CARBOXYPEPTIDASE L / CATHEPSIN A / PROTECTIVE PROTEIN CATHEPSIN A / PPCA / PROTECTIVE PROTEIN FOR BETA-GALACTOSIDASE


Mass: 51829.359 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: ACTIVATED WITH TRYPSIN-SEPHAROSE / Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P10619, carboxypeptidase C
#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE

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Non-polymers , 5 types, 620 molecules

#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 614 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
Sequence detailsAT THE C-TERMINUS, ONE EXTRA GLU IS PRESENT AS A LEFTOVER FROM A MYC-TAG

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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: 2.34 Å3/Da / Density % sol: 47.4 % / Description: NONE
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: CATHEPSIN A WAS CRYSTALLIZED USING THE HANGING DROP METHOD: 1 UL OF PROTEIN SOLUTION, CONTAINING 6.5 MG/ML CATHEPSIN A, 25 MM TRIS-HCL (PH 8.0) AND 300 MM NACL, WAS MIXED WITH 1 UL RESERVOIR ...Details: CATHEPSIN A WAS CRYSTALLIZED USING THE HANGING DROP METHOD: 1 UL OF PROTEIN SOLUTION, CONTAINING 6.5 MG/ML CATHEPSIN A, 25 MM TRIS-HCL (PH 8.0) AND 300 MM NACL, WAS MIXED WITH 1 UL RESERVOIR SOLUTION, CONTAINING 100 MM NAACETATE (PH 4.5), 18-20% PEG400 AND 100 MM CDCL2, AND SET TO EQUILIBRATE AT 4DEG.C. ROD-SHAPED CRYSTALS APPEARED IN ABOUT ONE WEEK.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1
DetectorType: DECTRIS PILATUS / Detector: PIXEL / Date: Mar 12, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.58→33.44 Å / Num. obs: 56973 / % possible obs: 96.6 % / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Biso Wilson estimate: 19.14 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 18.1
Reflection shellResolution: 1.58→1.66 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.35 / Mean I/σ(I) obs: 2.3 / % possible all: 94.3

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4AZ0

4az0


Resolution: 1.58→33.44 Å / Cor.coef. Fo:Fc: 0.9584 / Cor.coef. Fo:Fc free: 0.9471 / SU R Cruickshank DPI: 0.083 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.089 / SU Rfree Blow DPI: 0.085 / SU Rfree Cruickshank DPI: 0.081
RfactorNum. reflection% reflectionSelection details
Rfree0.1905 2843 5 %RANDOM
Rwork0.1649 ---
obs0.1662 56890 96.52 %-
Displacement parametersBiso mean: 23.01 Å2
Baniso -1Baniso -2Baniso -3
1-3.1215 Å20 Å22.4778 Å2
2--0.3008 Å20 Å2
3----3.4223 Å2
Refine analyzeLuzzati coordinate error obs: 0.165 Å
Refinement stepCycle: LAST / Resolution: 1.58→33.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3302 0 84 614 4000
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0073576HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.914882HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1213SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes99HARMONIC2
X-RAY DIFFRACTIONt_gen_planes520HARMONIC5
X-RAY DIFFRACTIONt_it3576HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.84
X-RAY DIFFRACTIONt_other_torsion16.59
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion441SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies12HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4641SEMIHARMONIC4
LS refinement shellResolution: 1.58→1.62 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.234 202 5.07 %
Rwork0.2196 3780 -
all0.2204 3982 -
obs--96.52 %

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