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- PDB-5ux4: Crystal Structure of Rat Cathepsin D with (5S)-3-(5,6-dihydro-2H-... -

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Basic information

Entry
Database: PDB / ID: 5ux4
TitleCrystal Structure of Rat Cathepsin D with (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro- 7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3- c]pyridine-5,4'-[1,3]oxazol]-2'-amine
ComponentsCathepsin D
KeywordsHYDROLASE / Cathepsin D / Beta Amyloid Cleaving Enzyme / BACE1
Function / homology
Function and homology information


Collagen degradation / cathepsin D / aspartic-type peptidase activity / Metabolism of Angiotensinogen to Angiotensins / regulation of establishment of protein localization / MHC class II antigen presentation / lipoprotein catabolic process / Neutrophil degranulation / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / autophagosome assembly ...Collagen degradation / cathepsin D / aspartic-type peptidase activity / Metabolism of Angiotensinogen to Angiotensins / regulation of establishment of protein localization / MHC class II antigen presentation / lipoprotein catabolic process / Neutrophil degranulation / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / autophagosome assembly / response to nutrient levels / peptide binding / melanosome / peptidase activity / endopeptidase activity / aspartic-type endopeptidase activity / endosome membrane / lysosome / hydrolase activity / membrane raft / positive regulation of apoptotic process / lysosomal membrane / proteolysis / extracellular space
Similarity search - Function
Cathepsin D / Aspartic peptidase, N-terminal / A1 Propeptide / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Eukaryotic aspartyl protease / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site ...Cathepsin D / Aspartic peptidase, N-terminal / A1 Propeptide / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Eukaryotic aspartyl protease / 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-3UT / Cathepsin D
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.805 Å
AuthorsSickmier, A.
CitationJournal: Medchemcomm / Year: 2017
Title: Development of 2-aminooxazoline 3-azaxanthene beta-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D.
Authors: Low, J.D. / Bartberger, M.D. / Chen, K. / Cheng, Y. / Fielden, M.R. / Gore, V. / Hickman, D. / Liu, Q. / Allen Sickmier, E. / Vargas, H.M. / Werner, J. / White, R.D. / Whittington, D.A. / ...Authors: Low, J.D. / Bartberger, M.D. / Chen, K. / Cheng, Y. / Fielden, M.R. / Gore, V. / Hickman, D. / Liu, Q. / Allen Sickmier, E. / Vargas, H.M. / Werner, J. / White, R.D. / Whittington, D.A. / Wood, S. / Minatti, A.E.
History
DepositionFeb 22, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 13, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 29, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
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.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 / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _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 2.1Oct 4, 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

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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)95,6368
Polymers93,6512
Non-polymers1,9856
Water45025
1
A: Cathepsin D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,9204
Polymers46,8261
Non-polymers1,0943
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cathepsin D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,7164
Polymers46,8261
Non-polymers8913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)136.514, 66.122, 99.555
Angle α, β, γ (deg.)90.000, 99.530, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Cathepsin D


Mass: 46825.523 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Ctsd / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P24268, cathepsin D
#2: 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
#3: 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.: 3
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
#4: Chemical ChemComp-3UT / (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazol]-2'-amine


Mass: 448.422 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H18F2N4O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 48.01 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 20% PEG 3350, 2% glycerol, 200 mM Lithium chloride cryo 20% glycerol, 20% PEG 3350, 200 mM lithium chloride

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Data collection

DiffractionMean temperature: 180 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Nov 8, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 21453 / % possible obs: 99.4 % / Redundancy: 3.6 % / Biso Wilson estimate: 47.07 Å2 / Rmerge(I) obs: 0.095 / Χ2: 1.014 / Net I/σ(I): 9.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsΧ2Diffraction-ID% possible all
2.8-2.93.30.3910.874196.7
2.9-3.023.60.3090.888199.2
3.02-3.153.70.2340.962199.7
3.15-3.323.70.1751.046199.6
3.32-3.533.70.131.039199.7
3.53-3.83.70.11.014199.8
3.8-4.183.70.0811.093199.9
4.18-4.783.70.0651.058199.8
4.78-6.023.60.0711.09199.5
6.02-303.50.061.048199.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
PHASERphasing
PHENIX1.11_2558refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1LYA

1lya


Resolution: 2.805→29.675 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 25.06
RfactorNum. reflection% reflection
Rfree0.2375 1098 5.12 %
Rwork0.1912 --
obs0.1937 21444 98.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 116.11 Å2 / Biso mean: 46.7496 Å2 / Biso min: 14.84 Å2
Refinement stepCycle: final / Resolution: 2.805→29.675 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5244 0 136 25 5405
Biso mean--64.22 36.47 -
Num. residues----677
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0035534
X-RAY DIFFRACTIONf_angle_d0.6987529
X-RAY DIFFRACTIONf_chiral_restr0.045829
X-RAY DIFFRACTIONf_plane_restr0.004944
X-RAY DIFFRACTIONf_dihedral_angle_d15.0953223
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8046-2.93210.31031240.22562398252294
2.9321-3.08660.33711400.23825192659100
3.0866-3.27970.28421270.229825612688100
3.2797-3.53260.24551360.214625352671100
3.5326-3.88740.25661340.199825782712100
3.8874-4.44830.20731440.165625622706100
4.4483-5.59820.18991570.152525462703100
5.5982-29.67670.22631360.18822647278399

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