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- PDB-4obz: Structure of Cathepsin D with inhibitor 2-(3,4-dimethoxyphenyl)-N... -

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Basic information

Entry
Database: PDB / ID: 4obz
TitleStructure of Cathepsin D with inhibitor 2-(3,4-dimethoxyphenyl)-N-[N-(4-methylbenzyl)carbamimidoyl]acetamide
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-2S4 / Cathepsin D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.9 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 8, 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 / 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 / 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 / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_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)76,6157
Polymers75,6284
Non-polymers9873
Water68538
1
C: Cathepsin D light chain
D: Cathepsin D heavy chain
hetero molecules

A: Cathepsin D light chain
B: Cathepsin D heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,6157
Polymers75,6284
Non-polymers9873
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
Buried area15570 Å2
ΔGint-87 kcal/mol
Surface area28030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)230.340, 42.454, 73.216
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, 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: 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 , 2 types, 39 molecules

#5: Chemical ChemComp-2S4 / 2-(3,4-dimethoxyphenyl)-N-[N-(4-methylbenzyl)carbamimidoyl]acetamide


Mass: 341.404 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23N3O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / 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: 2.37 Å3/Da / Density % sol: 48.03 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 5.5
Details: 35% PEG2000, 0.1 M KCl, 0.1 M KSCN, 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: 0.9999 / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 5, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.9→115.17 Å / Num. obs: 16536 / % possible obs: 99 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 0 / Redundancy: 5.9 % / Biso Wilson estimate: 73.75 Å2 / Rmerge(I) obs: 0.113 / Net I/σ(I): 5.7
Reflection shellResolution: 2.9→3.07 Å / Redundancy: 5.04 % / Rmerge(I) obs: 0.478 / Mean I/σ(I) obs: 2.96 / % possible all: 95.5

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
SCALAdata scaling
RefinementResolution: 2.9→45.26 Å / Cor.coef. Fo:Fc: 0.8955 / Cor.coef. Fo:Fc free: 0.8622 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2325 678 4.09 %RANDOM
Rwork0.1766 ---
obs0.1788 16558 98.94 %-
Displacement parametersBiso mean: 55.48 Å2
Baniso -1Baniso -2Baniso -3
1--20.19 Å20 Å20 Å2
2--2.0434 Å20 Å2
3---18.1466 Å2
Refine analyzeLuzzati coordinate error obs: 0.366 Å
Refinement stepCycle: LAST / Resolution: 2.9→45.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5202 0 67 38 5307
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015409HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.247352HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1810SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes120HARMONIC2
X-RAY DIFFRACTIONt_gen_planes779HARMONIC5
X-RAY DIFFRACTIONt_it5409HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.85
X-RAY DIFFRACTIONt_other_torsion21.66
X-RAY DIFFRACTIONt_chiral_improper_torsion697SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact5897SEMIHARMONIC4
LS refinement shellResolution: 2.9→3.1 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2852 116 4.09 %
Rwork0.2054 2723 -
all0.2086 2839 -
obs--98.94 %
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)
13.0844-1.2431-0.16683.3227-1.44074.0741-0.02480.31370.1066-0.1392-0.0420.04530.22960.26950.0668-0.1722-0.0142-0.04570.23410.11220.1021-28.220.187-29.053
21.77640.2193-0.97911.981-1.06363.5445-0.0790.10260.26370.16290.32030.52720.0794-0.481-0.2413-0.02720.0353-0.01770.39120.15310.4369-44.0951.479-15.758
33.3631-0.73240.30260-1.77423.3552-0.0741-0.09920.21670.31350.19130.2928-0.4366-0.5054-0.11720.14080.05040.00510.09390.03420.1047-24.95317.91711.32
41.65920.3819-0.59980.8779-0.70083.5468-0.01760.0655-0.01870.10690.0613-0.06070.05880.1441-0.04380.04650.0413-0.05530.09920.01770.0419-7.04619.9940.434
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|2 - A|97 }A2 - 97
2X-RAY DIFFRACTION2{ B|107 - B|346 }B107 - 346
3X-RAY DIFFRACTION3{ C|1 - C|97 }C1 - 97
4X-RAY DIFFRACTION4{ D|106 - D|346 }D106 - 346

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