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- PDB-5lu9: Crystal structure of YVAD-cmk bound human legumain (AEP) in compl... -

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Basic information

Entry
Database: PDB / ID: 5lu9
TitleCrystal structure of YVAD-cmk bound human legumain (AEP) in complex with compound 11
Components
  • AC-TYR-VAL-ALA-ASP-CHLOROMETHYLKETONE
  • LegumainAsparagine endopeptidase
KeywordsHYDROLASE / CYSTEINE PROTEASE / ALLOSTERIC INHIBITOR / ASPARAGINYL ENDOPEPTIDASE / ALZHEIMER'S DISEASE
Function / homology
Function and homology information


negative regulation of ERBB signaling pathway / legumain / vacuolar protein processing / renal system process / Vitamin D (calciferol) metabolism / receptor catabolic process / vitamin D metabolic process / self proteolysis / endolysosome lumen / activation of cysteine-type endopeptidase activity ...negative regulation of ERBB signaling pathway / legumain / vacuolar protein processing / renal system process / Vitamin D (calciferol) metabolism / receptor catabolic process / vitamin D metabolic process / self proteolysis / endolysosome lumen / activation of cysteine-type endopeptidase activity / positive regulation of endothelial cell chemotaxis / response to acidic pH / dendritic spine organization / positive regulation of monocyte chemotaxis / Trafficking and processing of endosomal TLR / negative regulation of multicellular organism growth / cellular response to hepatocyte growth factor stimulus / associative learning / protein maturation / endopeptidase activator activity / cellular response to calcium ion / MHC class II antigen presentation / lysosomal lumen / proteolysis involved in protein catabolic process / positive regulation of mitotic cell cycle / positive regulation of long-term synaptic potentiation / tau protein binding / memory / cellular response to amyloid-beta / antigen processing and presentation of exogenous peptide antigen via MHC class II / late endosome / apical part of cell / peptidase activity / negative regulation of neuron apoptotic process / lysosome / cysteine-type endopeptidase activity / negative regulation of gene expression / positive regulation of cell population proliferation / perinuclear region of cytoplasm / proteolysis / extracellular exosome / extracellular region / cytoplasm
Similarity search - Function
: / Legumain, prodomain / Legumain prodomain superfamily / Asparaginyl endopeptidase / Peptidase C13, legumain / Peptidase C13 family / Rossmann fold - #1460 / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
ACE-TYR-VAL-ALA-ASP-CHLOROMETHYLKETONE / 7-(morpholin-4-yl)-2,1,3-benzoxadiazol-4-amine / Legumain
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.27 Å
AuthorsDall, E. / Ye, K. / Brandstetter, H.
CitationJournal: Nat Commun / Year: 2017
Title: Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease.
Authors: Zhang, Z. / Obianyo, O. / Dall, E. / Du, Y. / Fu, H. / Liu, X. / Kang, S.S. / Song, M. / Yu, S.P. / Cabrele, C. / Schubert, M. / Li, X. / Wang, J.Z. / Brandstetter, H. / Ye, K.
History
DepositionSep 8, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 29, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2017Group: Database references
Revision 1.2Jun 13, 2018Group: Data collection / Structure summary / Category: pdbx_molecule_features
Revision 1.3Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_validate_torsion / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id
Revision 2.1Jan 17, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: AC-TYR-VAL-ALA-ASP-CHLOROMETHYLKETONE
A: Legumain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,4827
Polymers30,6272
Non-polymers8555
Water1,26170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2100 Å2
ΔGint-19 kcal/mol
Surface area11650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.390, 64.390, 79.330
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number77
Space group name H-MP42

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Components

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Protein/peptide / Protein / Sugars , 3 types, 4 molecules CA

#1: Protein/peptide AC-TYR-VAL-ALA-ASP-CHLOROMETHYLKETONE


Type: Peptide-like / Class: Inhibitor / Mass: 524.996 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: Ac-YVAD-chloromethyleketone inhibitor / Source: (synth.) synthetic construct (others) / References: ACE-TYR-VAL-ALA-ASP-CHLOROMETHYLKETONE
#2: Protein Legumain / Asparagine endopeptidase / Asparaginyl endopeptidase / Protease / cysteine 1


Mass: 30101.775 Da / Num. of mol.: 1 / Fragment: UNP Residues 26-288
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LGMN, PRSC1 / Production host: Leishmania tarentolae (eukaryote) / References: UniProt: Q99538, legumain
#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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
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, 73 molecules

#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-3Y7 / 7-(morpholin-4-yl)-2,1,3-benzoxadiazol-4-amine


Mass: 220.228 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H12N4O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 70 / 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: 2.68 Å3/Da / Density % sol: 54.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M HEPES PH 7.5, 0.2 M LITHIUM SULFATE MONOHYDRATE, 25 % PEG 3350, VAPOR DIFFUSION, SITTING DROP
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: May 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873 Å / Relative weight: 1
ReflectionResolution: 2.2→45.5 Å / Num. obs: 16546 / % possible obs: 100 % / Redundancy: 9.9 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 3.3
Reflection shellResolution: 2.2→2.3 Å / Redundancy: 9.3 % / Rmerge(I) obs: 0.71 / Mean I/σ(I) obs: 3.3 / CC1/2: 0.84 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4AWA
Resolution: 2.27→45.5 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.898 / SU B: 7.473 / SU ML: 0.186 / Cross valid method: THROUGHOUT / ESU R: 0.398 / ESU R Free: 0.26 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.273 745 5.1 %RANDOM
Rwork0.244 ---
obs0.245 13753 96.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 39.37 Å2
Baniso -1Baniso -2Baniso -3
1-0.23 Å20 Å20 Å2
2--0.23 Å20 Å2
3----0.45 Å2
Refinement stepCycle: LAST / Resolution: 2.27→45.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2150 0 54 70 2274
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0192265
X-RAY DIFFRACTIONr_bond_other_d0.0010.022035
X-RAY DIFFRACTIONr_angle_refined_deg1.081.9583077
X-RAY DIFFRACTIONr_angle_other_deg0.72334675
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6455263
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.41324.505111
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.92215360
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.533158
X-RAY DIFFRACTIONr_chiral_restr0.0570.2322
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022567
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02544
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_it1.3943.8111065
X-RAY DIFFRACTIONr_mcbond_other1.3933.8111065
X-RAY DIFFRACTIONr_mcangle_it2.3825.7051323
X-RAY DIFFRACTIONr_mcangle_other2.3815.7071324
X-RAY DIFFRACTIONr_scbond_it1.2814.0691199
X-RAY DIFFRACTIONr_scbond_other1.284.071200
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.166.0231744
X-RAY DIFFRACTIONr_long_range_B_refined3.81831.2532624
X-RAY DIFFRACTIONr_long_range_B_other3.81831.2632625
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.27→2.33 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 59 -
Rwork0.3 1041 -
obs--99.82 %

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