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- PDB-4az0: crystal structure of cathepsin a, complexed with 8a. -

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Basic information

Entry
Database: PDB / ID: 4az0
Titlecrystal structure of cathepsin a, complexed with 8a.
Components(LYSOSOMAL PROTECTIVE PROTEIN ...) x 2
KeywordsHYDROLASE / DRUG DISCOVERY / CARDIOVASCULAR DRUG
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 / enzyme activator activity / MHC class II antigen presentation ...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 / enzyme activator activity / MHC class II antigen presentation / lysosomal lumen / 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-S61 / Lysosomal protective protein
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 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_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.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

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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)53,75411
Polymers51,8472
Non-polymers1,9079
Water5,549308
1
A: LYSOSOMAL PROTECTIVE PROTEIN 32 KDA CHAIN
B: LYSOSOMAL PROTECTIVE PROTEIN 20 KDA CHAIN
hetero molecules

A: LYSOSOMAL PROTECTIVE PROTEIN 32 KDA CHAIN
B: LYSOSOMAL PROTECTIVE PROTEIN 20 KDA CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,50822
Polymers103,6954
Non-polymers3,81318
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,y,-z1
Buried area23930 Å2
ΔGint-201.4 kcal/mol
Surface area32070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.530, 101.638, 48.179
Angle α, β, γ (deg.)90.00, 101.97, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-2144-

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 / 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: 33773.734 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: Protein LYSOSOMAL PROTECTIVE PROTEIN 20 KDA CHAIN / 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: 18073.738 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

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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, 315 molecules

#4: Chemical ChemComp-S61 / (S)-3-{[1-(2-Fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-3-o-tolyl-propionic acid


Mass: 383.373 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18FN3O4
#5: Chemical
ChemComp-CD / CADMIUM ION


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


Mass: 18.015 Da / Num. of mol.: 308 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsAT THE C-TERMINUS, ONE EXTRA GLU IS PRESENT AS A LEFTOVER

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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: 2.3 Å3/Da / Density % sol: 46.6 % / 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: ID29 / Wavelength: 0.9762
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 6, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2.16→66.46 Å / Num. obs: 22196 / % possible obs: 96.9 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 37.16 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 14.6
Reflection shellResolution: 2.16→2.26 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 3.5 / % possible all: 79.2

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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: 2.17→44.28 Å / Cor.coef. Fo:Fc: 0.9494 / Cor.coef. Fo:Fc free: 0.9267 / SU R Cruickshank DPI: 0.27 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.284 / SU Rfree Blow DPI: 0.194 / SU Rfree Cruickshank DPI: 0.193
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=CD. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=3670. 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=3670. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=0. NUMBER TREATED BY BAD NON-BONDED CONTACTS=6.
Num. reflection% reflectionSelection details
Rfree1106 4.98 %RANDOM
obs22193 98.22 %-
Displacement parametersBiso mean: 37.98 Å2
Baniso -1Baniso -2Baniso -3
1--1.0598 Å20 Å20.0409 Å2
2---1.1108 Å20 Å2
3---2.1705 Å2
Refine analyzeLuzzati coordinate error obs: 0.235 Å
Refinement stepCycle: LAST / Resolution: 2.17→44.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3278 0 90 308 3676
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0073463HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.954721HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1158SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes94HARMONIC2
X-RAY DIFFRACTIONt_gen_planes518HARMONIC5
X-RAY DIFFRACTIONt_it3463HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.36
X-RAY DIFFRACTIONt_other_torsion16.88
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion429SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4190SEMIHARMONIC4
LS refinement shellResolution: 2.17→2.28 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2892 147 5.44 %
Rwork0.2299 2554 -
all0.233 2701 -
obs--98.22 %

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