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- PDB-7fqi: Crystal Structure of human Legumain in complex with (2S)-N-[(1S)-... -

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Basic information

Entry
Database: PDB / ID: 7fqi
TitleCrystal Structure of human Legumain in complex with (2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-[1-[4-[(2,4-difluorophenyl)methoxy]phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide
ComponentsLegumainAsparagine endopeptidase
KeywordsHYDROLASE/INHIBITOR / CYSTEINE PROTEASE / ALLOSTERIC INHIBITOR / ASPARAGINYL ENDOPEPTIDASE / ALZHEIMER'S DISEASE / HYDROLASE / HYDROLASE-INHIBITOR complex
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 / proteolysis involved in protein catabolic process / positive regulation of mitotic cell cycle / lysosomal lumen / 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
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsEhler, A. / Benz, J. / Bartels, B. / Rudolph, M.G.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
F. Hoffmann-La Roche Switzerland
CitationJournal: To be published
Title: Crystal Structure of a human Legumain complex
Authors: Bartels, B. / Kuhn, B. / Benz, J. / Rudolph, M.G.
History
DepositionOct 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / 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_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Legumain
B: Legumain
C: Legumain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)155,71214
Polymers152,6333
Non-polymers3,07911
Water11,367631
1
A: Legumain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,9876
Polymers50,8781
Non-polymers1,1095
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Legumain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,8013
Polymers50,8781
Non-polymers9232
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Legumain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,9255
Polymers50,8781
Non-polymers1,0474
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)229.510, 67.093, 79.120
Angle α, β, γ (deg.)90.000, 100.630, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Legumain / Asparagine endopeptidase / Asparaginyl endopeptidase / Protease / cysteine 1


Mass: 50877.672 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LGMN, PRSC1 / Plasmid: pExpreS2.1_hLGMN(18-433)_C-VD-8xHis / Production host: Drosophila melanogaster (fruit fly) / Strain (production host): ExpreS2 / References: UniProt: Q99538, legumain
#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.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#3: Chemical ChemComp-WSN / N-[(2R)-4-amino-1-imino-4-oxobutan-2-yl]-1-(1-{4-[(2,4-difluorophenyl)methoxy]phenyl}cyclopropane-1-carbonyl)-L-prolinamide


Mass: 498.522 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H28F2N4O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 631 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.03 Å3/Da / Density % sol: 39.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 23.4mg/mL deglycosylated protein in 25mM HEPES/NaOH pH7, 300 mM NaCl, 200mM Trehalose incubated with 10-fold excess of ligand, then mixed 50-70% with 50-30% reservoir consisting of 25% v/v ...Details: 23.4mg/mL deglycosylated protein in 25mM HEPES/NaOH pH7, 300 mM NaCl, 200mM Trehalose incubated with 10-fold excess of ligand, then mixed 50-70% with 50-30% reservoir consisting of 25% v/v PEG smear broad, 0.1M Bicine/NaOH pH 9.0, 10% v/v 2-Propanol, total volume 200nL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99982 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Mar 22, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99982 Å / Relative weight: 1
ReflectionResolution: 1.45→70.37 Å / Num. obs: 207573 / % possible obs: 99.3 % / Redundancy: 3.447 % / Biso Wilson estimate: 31.763 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.052 / Rrim(I) all: 0.062 / Χ2: 0.861 / Net I/σ(I): 9.71 / Num. measured all: 715549 / Scaling rejects: 143
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.45-1.493.4222.6140.45220615422152580.1683.09698.9
1.49-1.533.3441.810.64985615064149080.2972.15499
1.53-1.573.2281.3470.814669014580144640.3961.61899.2
1.57-1.623.3811.0471.094763714174140880.5411.24399.4
1.62-1.673.5910.8111.54905113754136610.6690.95299.3
1.67-1.733.5760.6062.024722213296132070.7730.71299.3
1.73-1.83.5550.4552.634528912821127400.8590.53699.4
1.8-1.873.5210.3193.74327612353122920.9220.37699.5
1.87-1.963.4790.2285.124113611893118250.9590.2799.4
1.96-2.053.3780.1597.123806011342112670.9740.18999.3
2.05-2.163.2230.119.63452010806107110.9860.13299.1
2.16-2.293.4110.08313.043463310205101530.9930.09999.5
2.29-2.453.6520.07116.0334972961295750.9950.08399.6
2.45-2.653.6340.05619.9232365895689070.9960.06699.5
2.65-2.93.5760.04424.5229346825082060.9970.05299.5
2.9-3.243.4970.03529.226092751174620.9980.04199.3
3.24-3.743.2890.02735.0421527660865460.9990.03299.1
3.74-4.593.2060.02438.2417722560655280.9990.02898.6
4.59-6.483.6150.02541.0215697437943420.9990.02999.2
6.48-70.373.3920.02441.738252246624330.9990.02898.7

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 1.45→70.37 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.958 / SU B: 1.36 / SU ML: 0.049 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.074 / ESU R Free: 0.074 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: Ligand in chain B has alternate conformations for the difluorophenyl
RfactorNum. reflection% reflectionSelection details
Rfree0.1891 7076 5 %RANDOM
Rwork0.1668 ---
obs0.1679 134406 67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 80.63 Å2 / Biso mean: 21.328 Å2 / Biso min: 11.43 Å2
Baniso -1Baniso -2Baniso -3
1--0.09 Å2-0 Å2-0.01 Å2
2--0.03 Å2-0 Å2
3---0.06 Å2
Refinement stepCycle: final / Resolution: 1.45→70.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6350 0 3111 634 10095
Biso mean--22.68 30.83 -
Num. residues----428
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0136924
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176202
X-RAY DIFFRACTIONr_angle_refined_deg1.5181.6679408
X-RAY DIFFRACTIONr_angle_other_deg1.4181.62414338
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7795825
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.38923.451368
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.667151126
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5041527
X-RAY DIFFRACTIONr_chiral_restr0.0790.2879
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.027886
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021617
X-RAY DIFFRACTIONr_mcbond_it1.3841.9983192
X-RAY DIFFRACTIONr_mcbond_other1.3831.9973191
X-RAY DIFFRACTIONr_mcangle_it2.0582.993993
LS refinement shellResolution: 1.445→1.483 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.354 19 -
Rwork0.311 290 -
all-309 -
obs--1.99 %

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