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- PDB-4od9: Structure of Cathepsin D with inhibitor N-(3,4-dimethoxybenzyl)-N... -

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Basic information

Entry
Database: PDB / ID: 4od9
TitleStructure of Cathepsin D with inhibitor N-(3,4-dimethoxybenzyl)-Nalpha-{N-[(3,4-dimethoxyphenyl)acetyl]carbamimidoyl}-D-phenylalaninamide
Components
  • Cathepsin D heavy chain
  • Cathepsin D light chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / LYSOSOMAL ASPARTIC PROTEASE / HYDROLASE-HYDROLASE INHIBITOR complex
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-2RZ / ACETATE ION / Cathepsin D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsGraedler, U. / Czodrowski, P. / Tsaklakidis, C. / Klein, M. / Maskos, K. / Leuthner, B.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Structure-based optimization of non-peptidic Cathepsin D inhibitors.
Authors: Gradler, U. / Czodrowski, P. / Tsaklakidis, C. / Klein, M. / Werkmann, D. / Lindemann, S. / Maskos, K. / Leuthner, B.
History
DepositionJan 10, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 13, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2014Group: Database references
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / 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 / 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.type_symbol / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.id / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.comp_id / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _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.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin D light chain
B: Cathepsin D heavy chain
C: Cathepsin D light chain
D: Cathepsin D heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,88611
Polymers75,6284
Non-polymers2,2577
Water9,008500
1
A: Cathepsin D light chain
B: Cathepsin D heavy chain
hetero molecules

C: Cathepsin D light chain
D: Cathepsin D heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,88611
Polymers75,6284
Non-polymers2,2577
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_655x+1,y,z1
Buried area17880 Å2
ΔGint-83 kcal/mol
Surface area26890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.480, 73.100, 234.190
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 4 molecules ACBD

#1: Protein Cathepsin D light chain


Mass: 11273.560 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CPSD, CTSD / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07339, cathepsin D
#2: Protein Cathepsin D heavy chain


Mass: 26540.561 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CPSD, CTSD / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07339, cathepsin D

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Sugars , 2 types, 3 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
#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose


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 , 3 types, 504 molecules

#4: Chemical ChemComp-2RZ / N-(3,4-dimethoxybenzyl)-Nalpha-{N-[(3,4-dimethoxyphenyl)acetyl]carbamimidoyl}-D-phenylalaninamide


Mass: 534.603 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H34N4O6
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 500 / 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: 2.4 Å3/Da / Density % sol: 48.83 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 5.5
Details: 35% PEG2000, 0,1 M KCl, 0.1 M Na-Acetat (pH 5.5), VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.999 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 1.9→45.7 Å / Num. all: 58340 / % possible obs: 99.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): -3 / Redundancy: 5.97 % / Biso Wilson estimate: 20.51 Å2 / Rmerge(I) obs: 0.139
Reflection shellResolution: 1.9→2.01 Å / Rmerge(I) obs: 0.486 / Mean I/σ(I) obs: 3.09 / Num. unique all: 9190 / % possible all: 97.9

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Processing

Software
NameVersionClassification
XDSdata scaling
PHASERphasing
BUSTER2.11.4refinement
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→38 Å / Cor.coef. Fo:Fc: 0.9239 / Cor.coef. Fo:Fc free: 0.9104 / SU R Cruickshank DPI: 0.143 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2165 2916 5 %RANDOM
Rwork0.1833 ---
obs0.185 58324 99.27 %-
Displacement parametersBiso mean: 23.81 Å2
Baniso -1Baniso -2Baniso -3
1--2.6061 Å20 Å20 Å2
2---2.9351 Å20 Å2
3---5.5412 Å2
Refine analyzeLuzzati coordinate error obs: 0.216 Å
Refinement stepCycle: LAST / Resolution: 1.9→38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5192 0 156 500 5848
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015489HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.127461HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1850SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes124HARMONIC2
X-RAY DIFFRACTIONt_gen_planes792HARMONIC5
X-RAY DIFFRACTIONt_it5489HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion3.85
X-RAY DIFFRACTIONt_other_torsion17.6
X-RAY DIFFRACTIONt_chiral_improper_torsion709SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact6478SEMIHARMONIC4
LS refinement shellResolution: 1.9→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2432 208 5.01 %
Rwork0.1988 3946 -
all0.201 4154 -
obs-4154 99.27 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.784-0.15470.03471.01770.55572.072-0.0944-0.13540.05650.1150.045-0.0381-0.1249-0.05420.0494-0.02850.0482-0.0271-0.1365-0.00570.0643-0.711329.0127-28.975
20.4974-0.26680.18641.25460.35710.98280.00050.0398-0.0054-0.0704-0.02430.0626-0.0414-0.05940.0238-0.07860.0131-0.0133-0.11670.00920.0391-1.652115.445-45.0868
30.6329-0.18720.20311.77190.05951.62810.08750.0341-0.0885-0.1904-0.03220.10920.1290.007-0.0553-0.06020.0446-0.0228-0.1268-0.01390.0642-18.2861-12.0239-25.356
40.7378-0.5095-0.03351.10670.30390.9008-0.0208-0.08160.0090.02070.0503-0.0170.02830.0238-0.0295-0.1050.0101-0.0161-0.12690.00640.0602-20.7368-0.4428-7.9056
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|2 - A|98 A|101 - A|102 }A2 - 98
2X-RAY DIFFRACTION1{ A|2 - A|98 A|101 - A|102 }A101 - 102
3X-RAY DIFFRACTION2{ B|107 - B|346 B|401 - B|401 }B107 - 346
4X-RAY DIFFRACTION2{ B|107 - B|346 B|401 - B|401 }B401
5X-RAY DIFFRACTION3{ C|2 - C|98 C|400 - C|401 }C2 - 98
6X-RAY DIFFRACTION3{ C|2 - C|98 C|400 - C|401 }C400 - 401
7X-RAY DIFFRACTION4{ D|106 - D|346 }D106 - 346

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