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- PDB-4cib: crystal structure of cathepsin a, complexed with compound 2 -

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Basic information

Entry
Database: PDB / ID: 4cib
Titlecrystal structure of cathepsin a, complexed with compound 2
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 / intracellular protein transport / enzyme activator activity / 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
2-(cyclohexylmethyl)propanedioic acid / : / Lysosomal protective protein
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 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 / database_PDB_caveat / 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 / pdbx_validate_chiral / 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_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_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 / _pdbx_validate_chiral.auth_asym_id / _pdbx_validate_chiral.auth_seq_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 2.2Oct 23, 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

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Assembly

Deposited unit
A: LYSOSOMAL PROTECTIVE PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4409
Polymers51,8291
Non-polymers1,6118
Water16,358908
1
A: LYSOSOMAL PROTECTIVE PROTEIN
hetero molecules

A: LYSOSOMAL PROTECTIVE PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,88118
Polymers103,6592
Non-polymers3,22216
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,y,-z1
Buried area6650 Å2
ΔGint-53.7 kcal/mol
Surface area32770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.649, 102.527, 49.395
Angle α, β, γ (deg.)90.00, 100.94, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-2181-

HOH

21A-2308-

HOH

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Components

#1: Protein LYSOSOMAL PROTECTIVE PROTEIN / CATHEPSIN A / CARBOXYPEPTIDASE C / CARBOXYPEPTIDASE L / PROTECTIVE PROTEIN CATHEPSIN A / PPCA / ...CATHEPSIN A / CARBOXYPEPTIDASE C / CARBOXYPEPTIDASE L / 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)][a-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: Chemical ChemComp-7UZ / 2-(cyclohexylmethyl)propanedioic acid


Mass: 200.232 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16O4
#4: Chemical
ChemComp-CD / CADMIUM ION


Mass: 112.411 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cd
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 908 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence details2 EXTRA RESIDUES FROM PREPROMELLITIN SIGNAL SEQUENCE AT N- TERMINUS AND 1 EXTRA RESIDUE, LEFT OVER ...2 EXTRA RESIDUES FROM PREPROMELLITIN SIGNAL SEQUENCE AT N- TERMINUS AND 1 EXTRA RESIDUE, LEFT OVER FROM MYC TAG AT C- TERMINUS

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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: 2.42 Å3/Da / Density % sol: 49.2 % / 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: ESRF / Beamline: ID14-1 / Wavelength: 0.934
DetectorType: ADSC CCD / Detector: CCD / Date: Aug 29, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 1.89→66.74 Å / Num. obs: 35026 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 3.8 % / Biso Wilson estimate: 20.2 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 14.12
Reflection shellResolution: 1.89→1.94 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.35 / Mean I/σ(I) obs: 3.76 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4AZ0

4az0


Resolution: 1.89→44.02 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.919 / SU B: 2.815 / SU ML: 0.087 / Cross valid method: THROUGHOUT / ESU R: 0.14 / ESU R Free: 0.145 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.21073 1752 5 %RANDOM
Rwork0.14141 ---
obs0.14484 33271 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 18.551 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å20 Å2-0.09 Å2
2--0.05 Å20 Å2
3----0.03 Å2
Refinement stepCycle: LAST / Resolution: 1.89→44.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3292 0 75 908 4275
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0223460
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4091.9754710
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7555410
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.91124.911169
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.27415533
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2241512
X-RAY DIFFRACTIONr_chiral_restr0.0970.2501
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022679
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2070.21809
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3120.22343
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.190.2687
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1810.278
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2020.287
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.0110.21
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8031.52108
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.323305
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.05231558
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.1054.51405
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: 1.89→1.939 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.236 127 -
Rwork0.165 2414 -
obs--100 %

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