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- PDB-6qcb: Crystal structure of human cathepsin D in complex with macrocycli... -

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Basic information

Entry
Database: PDB / ID: 6qcb
TitleCrystal structure of human cathepsin D in complex with macrocyclic inhibitor 9
Components(Cathepsin D) x 2
KeywordsHYDROLASE / aspartic protease / peptidomimetic inhibitor
Function / homology
Function and homology information


cathepsin D / aspartic-type peptidase activity / regulation of establishment of protein localization / insulin catabolic process / lipoprotein catabolic process / execution phase of apoptosis / insulin receptor recycling / Collagen degradation / autophagosome assembly / Metabolism of Angiotensinogen to Angiotensins ...cathepsin D / aspartic-type peptidase activity / regulation of establishment of protein localization / insulin catabolic process / lipoprotein catabolic process / execution phase of apoptosis / insulin receptor recycling / Collagen degradation / autophagosome assembly / Metabolism of Angiotensinogen to Angiotensins / Insulin receptor recycling / MHC class II antigen presentation / lysosomal lumen / endosome lumen / antigen processing and presentation of exogenous peptide antigen via MHC class II / specific granule lumen / tertiary granule lumen / melanosome / peptidase activity / : / Estrogen-dependent gene expression / ficolin-1-rich granule lumen / aspartic-type endopeptidase activity / lysosome / endosome membrane / positive regulation of apoptotic process / membrane raft / lysosomal membrane / cysteine-type endopeptidase activity / Neutrophil degranulation / proteolysis / extracellular space / extracellular exosome / extracellular region / cytosol
Similarity search - Function
Cathepsin D / Aspartic peptidase, N-terminal / A1 Propeptide / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site ...Cathepsin D / Aspartic peptidase, N-terminal / A1 Propeptide / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-HWE / PHOSPHITE ION / Cathepsin D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsBrynda, J. / Houstecka, R. / Majer, P. / Mares, M.
Funding support Czech Republic, 3items
OrganizationGrant numberCountry
RVO 61388963 Czech Republic
European Regional Development FundCZ.02.1.01/0.0/0.0/16_019/0000729 Czech Republic
802218 Czech Republic
CitationJournal: J.Med.Chem. / Year: 2020
Title: Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure-Activity Relationship and Binding Mode Analysis.
Authors: Houstecka, R. / Hadzima, M. / Fanfrlik, J. / Brynda, J. / Pallova, L. / Hanova, I. / Mertlikova-Kaiserova, H. / Lepsik, M. / Horn, M. / Smrcina, M. / Majer, P. / Mares, M.
History
DepositionDec 27, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2020Group: Data collection / Database references / Category: chem_comp / citation / citation_author
Item: _chem_comp.type / _citation.country ..._chem_comp.type / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 11, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / 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 / 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.type_symbol / _chem_comp.name / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.src_method / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_special_symmetry.label_asym_id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.pdbx_value_order / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Jan 24, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin D
B: Cathepsin D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9079
Polymers37,0592
Non-polymers1,8487
Water5,801322
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8450 Å2
ΔGint-40 kcal/mol
Surface area15270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.346, 94.257, 117.675
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11B-722-

HOH

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Cathepsin D


Mass: 10688.941 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSD, CPSD / Production host: Homo sapiens (human) / References: UniProt: P07339, cathepsin D
#2: Protein Cathepsin D


Mass: 26370.348 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSD, CPSD / Production host: Homo sapiens (human) / References: UniProt: P07339, cathepsin D

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Sugars , 2 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.: 1
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
#4: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE

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Non-polymers , 5 types, 327 molecules

#5: Chemical ChemComp-PO3 / PHOSPHITE ION


Mass: 78.972 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO3
#6: Chemical ChemComp-HWE / (3~{S},7~{S},8~{S})-7-oxidanyl-8-(phenylmethyl)-3-propan-2-yl-1,4,9-triazacyclohenicosane-2,5,10-trione


Mass: 487.675 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H45N3O4
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 322 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 3.01 Å3/Da / Density % sol: 59.08 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop
Details: 25 % PEG 3350 0.2 lithium sulphate 0.1 Bis-Tris pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.55→50 Å / Num. obs: 62404 / % possible obs: 97.8 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.078 / Net I/σ(I): 12.5
Reflection shellResolution: 1.55→1.6 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.953 / Mean I/σ(I) obs: 1.02 / CC1/2: 0.622 / % possible all: 88.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6QBH

6qbh


Resolution: 1.55→43.75 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.957 / SU B: 1.452 / SU ML: 0.05 / Cross valid method: THROUGHOUT / ESU R: 0.066 / ESU R Free: 0.067 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18977 2101 3.3 %RANDOM
Rwork0.16637 ---
obs0.16713 62404 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 22.435 Å2
Baniso -1Baniso -2Baniso -3
1-0.65 Å2-0 Å20 Å2
2--0.39 Å20 Å2
3----1.04 Å2
Refinement stepCycle: 1 / Resolution: 1.55→43.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2592 0 120 322 3034
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.022921
X-RAY DIFFRACTIONr_bond_other_d0.0020.022732
X-RAY DIFFRACTIONr_angle_refined_deg1.742.0213996
X-RAY DIFFRACTIONr_angle_other_deg1.0723.0016358
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5625.026378
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.00724.821112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.54815465
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.704159
X-RAY DIFFRACTIONr_chiral_restr0.1010.2460
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213244
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02629
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_it1.4681.9421396
X-RAY DIFFRACTIONr_mcbond_other1.4671.9421397
X-RAY DIFFRACTIONr_mcangle_it2.1492.911752
X-RAY DIFFRACTIONr_mcangle_other2.1482.9111753
X-RAY DIFFRACTIONr_scbond_it2.5642.3791525
X-RAY DIFFRACTIONr_scbond_other2.5632.3781526
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.7693.4372225
X-RAY DIFFRACTIONr_long_range_B_refined5.18124.3513140
X-RAY DIFFRACTIONr_long_range_B_other5.18124.3533141
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.552→1.592 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 150 -
Rwork0.274 4457 -
obs--97.61 %

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