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- PDB-4cia: Crystal structure of cathepsin A, complexed with compound 1 -

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Basic information

Entry
Database: PDB / ID: 4cia
TitleCrystal structure of cathepsin A, complexed with compound 1
ComponentsLYSOSOMAL PROTECTIVE PROTEIN
KeywordsHYDROLASE / 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
Chem-6KZ / : / Lysosomal protective protein
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.98 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 1.3Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_database_status / pdbx_entity_nonpoly / pdbx_struct_conn_angle / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_role / _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_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 1.4Dec 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 1.5Oct 16, 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)53,51811
Polymers51,8291
Non-polymers1,68910
Water6,449358
1
A: LYSOSOMAL PROTECTIVE PROTEIN
hetero molecules

A: LYSOSOMAL PROTECTIVE PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,03622
Polymers103,6592
Non-polymers3,37820
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,y,-z1
Buried area6050 Å2
ΔGint-89.7 kcal/mol
Surface area31290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.106, 101.295, 48.077
Angle α, β, γ (deg.)90.00, 101.91, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-2009-

HOH

21A-2206-

HOH

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Components

#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: Chemical ChemComp-6KZ / N-[(2S)-4-methyl-1-oxidanylidene-1-[[(1R,2S)-1-oxidanyl-1-(5-phenyl-1,2,4-oxadiazol-3-yl)butan-2-yl]amino]pentan-2-yl]morpholine-4-carboxamide


Mass: 459.539 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H33N5O5
#3: Chemical
ChemComp-CD / CADMIUM ION


Mass: 112.411 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cd
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 358 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsAT THE N-TERMINUS, 2 RESIDUES FROM PREPROMELLITIN SIGNAL SEQUENCE ARE PRESENT, AT THE C-TERMINUS, 1 ...AT THE N-TERMINUS, 2 RESIDUES FROM PREPROMELLITIN SIGNAL SEQUENCE ARE PRESENT, AT THE C-TERMINUS, 1 RESIDUE LEFT OVER FROM THE MYC-TAG IS PRESENT.

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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: 46.5 % / 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: ID14-4 / Wavelength: 0.9395
DetectorType: ADSC CCD / Detector: CCD / Date: Sep 11, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9395 Å / Relative weight: 1
ReflectionResolution: 1.97→66.25 Å / Num. obs: 28737 / % possible obs: 96.2 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 11.47
Reflection shellResolution: 1.97→2.07 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.28 / Mean I/σ(I) obs: 4.12 / % possible all: 73.5

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4AZ0

4az0


Resolution: 1.98→36.11 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.905 / SU B: 4.15 / SU ML: 0.115 / Cross valid method: THROUGHOUT / ESU R: 0.188 / ESU R Free: 0.174 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.232 1437 5 %RANDOM
Rwork0.16991 ---
obs0.17292 27298 98.26 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.508 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å2-0 Å2-0.15 Å2
2--0.2 Å2-0 Å2
3----0.26 Å2
Refinement stepCycle: LAST / Resolution: 1.98→36.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3273 0 68 358 3699
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.023442
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.7061.9724685
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6215411
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.29224.819166
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.19715530
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4261512
X-RAY DIFFRACTIONr_chiral_restr0.1150.2491
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212693
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 1.984→2.035 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 84 -
Rwork0.263 1598 -
obs--78.75 %

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