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

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Basic information

Entry
Database: PDB / ID: 6qbh
TitleCrystal structure of human cathepsin D in complex with macrocyclic inhibitor 33
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 / insulin receptor recycling / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / 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 / insulin receptor recycling / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / Collagen degradation / autophagosome assembly / Metabolism of Angiotensinogen to Angiotensins / Insulin receptor recycling / MHC class II antigen presentation / lysosomal lumen / endosome lumen / specific granule lumen / antigen processing and presentation of exogenous peptide antigen via MHC class II / melanosome / tertiary granule lumen / peptidase activity / collagen-containing extracellular matrix / 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
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-S43 / Cathepsin D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 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 21, 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.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _pdbx_entity_nonpoly.comp_id / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_special_symmetry.label_asym_id / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_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

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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)38,3837
Polymers37,0592
Non-polymers1,3235
Water4,486249
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7690 Å2
ΔGint-38 kcal/mol
Surface area15090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.244, 94.136, 117.580
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-275-

HOH

21B-674-

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 natural source / Source: (natural) 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 natural source / Source: (natural) 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
#5: 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.: 1
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

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Non-polymers , 4 types, 252 molecules

#4: Chemical ChemComp-S43 / (4~{S},5~{S},9~{S})-5-oxidanyl-4-(phenylmethyl)-9-propan-2-yl-1-oxa-3,8,11-triazacyclodocosane-2,7,10-trione


Mass: 503.674 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H45N3O5
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / Source method: isolated from a natural source / Formula: H2O

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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 Å3/Da / Density % sol: 58.94 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop
Details: 25 % PEG 3350 0.2 M lithium sulphate 0.1 M 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: 1.85→50 Å / Num. obs: 32236 / % possible obs: 98.6 % / Redundancy: 3.6 % / CC1/2: 0.996 / Rmerge(I) obs: 0.109 / Net I/σ(I): 7.9
Reflection shellResolution: 1.85→1.9 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.964 / Mean I/σ(I) obs: 1.1 / CC1/2: 0.512 / % possible all: 97.4

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Processing

Software
NameVersionClassification
REFMACrefinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6QBG

6qbg


Resolution: 1.85→47.07 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.935 / SU B: 2.886 / SU ML: 0.083 / SU R Cruickshank DPI: 0.1311 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.131 / ESU R Free: 0.123
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2072 997 3 %RANDOM
Rwork0.1753 ---
obs0.1762 32236 86.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 63.38 Å2 / Biso mean: 20.035 Å2 / Biso min: 7.93 Å2
Baniso -1Baniso -2Baniso -3
1--0.19 Å2-0 Å20 Å2
2--0.29 Å2-0 Å2
3----0.1 Å2
Refinement stepCycle: final / Resolution: 1.85→47.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2597 0 95 250 2942
Biso mean--30.51 26.39 -
Num. residues----338
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0192789
X-RAY DIFFRACTIONr_bond_other_d0.0020.022621
X-RAY DIFFRACTIONr_angle_refined_deg1.6531.9973792
X-RAY DIFFRACTIONr_angle_other_deg0.96836076
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7215348
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.28624.679109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.9715443
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.752159
X-RAY DIFFRACTIONr_chiral_restr0.0930.2426
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213098
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02606
LS refinement shellResolution: 1.851→1.899 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.292 23 -
Rwork0.312 761 -
all-784 -
obs--27.84 %

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