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- PDB-4az3: crystal structure of cathepsin a, complexed with 15a -

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Basic information

Entry
Database: PDB / ID: 4az3
Titlecrystal structure of cathepsin a, complexed with 15a
Components(LYSOSOMAL PROTECTIVE PROTEIN ...) x 2
KeywordsHYDROLASE / DRUG DISCOVERY / CARBOXYPEPTIDASE / CARDIOVASCULAR
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
Rossmann fold - #12670 / 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 ...Rossmann fold - #12670 / 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
: / Chem-S35 / Lysosomal protective protein
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsRuf, S. / Buning, C. / Schreuder, H. / Horstick, G. / Linz, W. / Olpp, T. / Pernerstorfer, J. / Hiss, K. / Kroll, K. / Kannt, A. ...Ruf, S. / Buning, C. / Schreuder, H. / Horstick, G. / Linz, W. / Olpp, T. / Pernerstorfer, J. / Hiss, K. / Kroll, K. / Kannt, A. / Kohlmann, M. / Linz, D. / Huebschle, T. / Ruetten, H. / Wirth, K. / Schmidt, T. / Sadowski, T.
CitationJournal: 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
DepositionJun 22, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 26, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc ...exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_conn
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval / _struct_conn.pdbx_leaving_atom_flag
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow
Item: _exptl_crystal_grow.method
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...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_conn_angle / pdbx_struct_special_symmetry / 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_alt_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.pdbx_formal_charge / _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_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.ptnr1_symmetry / _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.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _pdbx_struct_special_symmetry.label_asym_id / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _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.ptnr1_symmetry / _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_conn.ptnr2_symmetry
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 13, 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 32 KDA CHAIN
B: LYSOSOMAL PROTECTIVE PROTEIN 20 KDA CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,6299
Polymers51,8472
Non-polymers1,7827
Water7,602422
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9920 Å2
ΔGint-83.5 kcal/mol
Surface area17930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.590, 102.800, 48.390
Angle α, β, γ (deg.)90.00, 101.87, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-2207-

HOH

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Components

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LYSOSOMAL PROTECTIVE PROTEIN ... , 2 types, 2 molecules AB

#1: Protein LYSOSOMAL PROTECTIVE PROTEIN 32 KDA CHAIN / LYSOSOMAL PROTECTIVE PROTEIN CARBOXYPEPTIDASE C / CARBOXYPEPTIDASE L / CATHEPSIN A / PROTECTIVE ...LYSOSOMAL PROTECTIVE PROTEIN CARBOXYPEPTIDASE C / CARBOXYPEPTIDASE L / CATHEPSIN A / PROTECTIVE PROTEIN CATHEPSIN A / PPCA / PROTECTIVE PROTEIN FOR BETA-GALACTOSIDASE


Mass: 33773.734 Da / Num. of mol.: 1 / Fragment: ACTIVATED PROTEASE RESIDUES 29-326
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: Protein LYSOSOMAL PROTECTIVE PROTEIN 20 KDA CHAIN / LYSOSOMAL PROTECTIVE PROTEIN CARBOXYPEPTIDASE C / CARBOXYPEPTIDASE L / CATHEPSIN A / PROTECTIVE ...LYSOSOMAL PROTECTIVE PROTEIN CARBOXYPEPTIDASE C / CARBOXYPEPTIDASE L / CATHEPSIN A / PROTECTIVE PROTEIN CATHEPSIN A / PPCA / PROTECTIVE PROTEIN FOR BETA-GALACTOSIDASE


Mass: 18073.738 Da / Num. of mol.: 1 / Fragment: ACTIVATED PROTEASE, RESIDUES 327-480
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

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Sugars , 1 types, 2 molecules

#3: 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 , 3 types, 427 molecules

#4: Chemical ChemComp-S35 / (3S)-3-({[1-(2-fluorophenyl)-5-{[(2R)-2-hydroxy-3,3-dimethylbutyl]oxy}-1H-pyrazol-3-yl]carbonyl}amino)-3-(2-methylphenyl)propanoic acid


Mass: 483.532 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30FN3O5
#5: Chemical
ChemComp-CD / CADMIUM ION


Mass: 112.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cd
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 422 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
Sequence detailsEXTRA C-TERMINAL GLU AS LEFTOVER FROM 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: 2.4 Å3/Da / Density % sol: 48.7 % / Description: NONE
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: CATA 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: CATA 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 4 DEG. C. ROD-SHAPED CRYSTALS APPEARED IN ABOUT ONE WEEK.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9395
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 17, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9395 Å / Relative weight: 1
ReflectionResolution: 2.04→67.1 Å / Num. obs: 27381 / % possible obs: 99 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 27.96 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 14.9
Reflection shellResolution: 2.04→2.1 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.35 / Mean I/σ(I) obs: 4 / % possible all: 99.1

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: MODEL DERIVED FROM PDB ENTRY 1IVY

1ivy


Resolution: 2.04→47.36 Å / Cor.coef. Fo:Fc: 0.9447 / Cor.coef. Fo:Fc free: 0.9265 / SU R Cruickshank DPI: 0.218 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.234 / SU Rfree Blow DPI: 0.167 / SU Rfree Cruickshank DPI: 0.164
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=CD. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=3850. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=0. ...Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=CD. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=3850. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=0. NUMBER TREATED BY BAD NON-BONDED CONTACTS=4.
RfactorNum. reflection% reflectionSelection details
Rfree0.215 1344 4.91 %RANDOM
Rwork0.188 ---
obs-27378 99.05 %-
Displacement parametersBiso mean: 28.88 Å2
Baniso -1Baniso -2Baniso -3
1--0.5078 Å20 Å20.1075 Å2
2---0.5904 Å20 Å2
3---1.0981 Å2
Refine analyzeLuzzati coordinate error obs: 0.244 Å
Refinement stepCycle: LAST / Resolution: 2.04→47.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3288 0 95 422 3805
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0073533HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.964823HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1183SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes95HARMONIC2
X-RAY DIFFRACTIONt_gen_planes507HARMONIC5
X-RAY DIFFRACTIONt_it3533HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.38
X-RAY DIFFRACTIONt_other_torsion16.46
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion436SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies3HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4443SEMIHARMONIC4
LS refinement shellResolution: 2.04→2.12 Å / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.2506 130 4.5 %
Rwork0.2405 2762 -
all0.2409 2892 -
obs--99.05 %

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