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- PDB-7a3j: Crystal structure of DPP8 in complex with a 4-oxo-b-lactam based ... -

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Basic information

Entry
Database: PDB / ID: 7a3j
TitleCrystal structure of DPP8 in complex with a 4-oxo-b-lactam based inhibitor, A272
ComponentsDipeptidyl peptidase 8
KeywordsHYDROLASE / DPP8 / Protease
Function / homology
Function and homology information


dipeptidyl-peptidase IV / dipeptidyl-peptidase activity / negative regulation of programmed cell death / aminopeptidase activity / serine-type peptidase activity / immune response / apoptotic process / proteolysis / cytosol / cytoplasm
Similarity search - Function
Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / : / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Chem-QXK / trimethylamine oxide / Dipeptidyl peptidase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsRoss, B.H. / Huber, R.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2022
Title: Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.
Authors: Carvalho, L.A.R. / Ross, B. / Fehr, L. / Bolgi, O. / Wohrle, S. / Lum, K.M. / Podlesainski, D. / Vieira, A.C. / Kiefersauer, R. / Felix, R. / Rodrigues, T. / Lucas, S.D. / Gross, O. / Geiss- ...Authors: Carvalho, L.A.R. / Ross, B. / Fehr, L. / Bolgi, O. / Wohrle, S. / Lum, K.M. / Podlesainski, D. / Vieira, A.C. / Kiefersauer, R. / Felix, R. / Rodrigues, T. / Lucas, S.D. / Gross, O. / Geiss-Friedlander, R. / Cravatt, B.F. / Huber, R. / Kaiser, M. / Moreira, R.
History
DepositionAug 18, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 30, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Dipeptidyl peptidase 8
A: Dipeptidyl peptidase 8
B: Dipeptidyl peptidase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)312,15512
Polymers310,4503
Non-polymers1,7059
Water50428
1
C: Dipeptidyl peptidase 8
B: Dipeptidyl peptidase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)208,1038
Polymers206,9672
Non-polymers1,1366
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4450 Å2
ΔGint-30 kcal/mol
Surface area64170 Å2
MethodPISA
2
A: Dipeptidyl peptidase 8
hetero molecules

A: Dipeptidyl peptidase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)208,1038
Polymers206,9672
Non-polymers1,1366
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area4420 Å2
ΔGint-34 kcal/mol
Surface area65170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)164.377, 252.959, 260.869
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Dipeptidyl peptidase 8 / DP8 / Dipeptidyl peptidase IV-related protein 1 / DPRP-1 / Dipeptidyl peptidase VIII / DPP VIII / ...DP8 / Dipeptidyl peptidase IV-related protein 1 / DPRP-1 / Dipeptidyl peptidase VIII / DPP VIII / Prolyl dipeptidase DPP8


Mass: 103483.352 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP8, DPRP1, MSTP097, MSTP135, MSTP141 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q6V1X1, dipeptidyl-peptidase IV
#2: Chemical ChemComp-QXK / 2-ethyl-2-methanoyl-~{N}-[3-[[4-(naphthalen-1-ylmethyl)piperazin-1-yl]methyl]phenyl]butanamide


Mass: 457.607 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C29H35N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-TMO / trimethylamine oxide


Mass: 75.110 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H9NO
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 4.37 Å3/Da / Density % sol: 71.84 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 0.46 M Na citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Nov 20, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→49.54 Å / Num. obs: 108427 / % possible obs: 100 % / Redundancy: 8.576 % / Biso Wilson estimate: 84.753 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.081 / Rrim(I) all: 0.086 / Χ2: 1.044 / Net I/σ(I): 18.5 / Num. measured all: 929839 / Scaling rejects: 118
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
3-3.088.5291.1252.268196799679960.8021.198100
3.08-3.168.1370.8312.8762713770877070.8620.888100
3.16-3.268.3260.6073.9665448786278610.9240.648100
3.26-3.378.6490.4335.4567865784878470.9610.461100
3.37-3.499.0520.3247.2770283776677640.980.344100
3.49-3.639.0060.2638.6969335770076990.9860.279100
3.63-3.88.9280.22210.270087785078500.9870.236100
3.8-4.018.8140.14414.567862769976990.9930.153100
4.01-4.268.6390.09420.0367047776177610.9970.1100
4.26-4.68.1350.06625.362580769376930.9990.071100
4.6-5.078.2870.05331.5263708768876880.9990.056100
5.07-5.838.9660.05432.6368830767776770.9990.057100
5.83-7.18.7030.0534.9658526672567250.9990.053100
7.1-97.9050.03347.4833508423942390.9990.035100
9-11.567.9960.02265.62176552209220810.023100
11.56-16.878.3160.02176.01113271362136210.022100
16.87-277.7570.0276.23390250550310.02199.6
27-49.546.5340.01974.849671851480.9990.02180

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6EOP

6eop


Resolution: 3→49.54 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.922 / SU B: 14.555 / SU ML: 0.254 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.567 / ESU R Free: 0.313 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2323 5422 5 %RANDOM
Rwork0.1969 ---
obs0.1987 103005 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 230.66 Å2 / Biso mean: 101.429 Å2 / Biso min: 30 Å2
Baniso -1Baniso -2Baniso -3
1-1.22 Å20 Å2-0 Å2
2--4.18 Å20 Å2
3----5.39 Å2
Refinement stepCycle: final / Resolution: 3→49.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms19949 0 120 28 20097
Biso mean--121.05 71.25 -
Num. residues----2459
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01920633
X-RAY DIFFRACTIONr_bond_other_d0.0010.0219161
X-RAY DIFFRACTIONr_angle_refined_deg1.1521.96228007
X-RAY DIFFRACTIONr_angle_other_deg0.853344182
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.13852450
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.10823.5791003
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.237153421
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4615131
X-RAY DIFFRACTIONr_chiral_restr0.0690.22965
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02123152
X-RAY DIFFRACTIONr_gen_planes_other0.0010.024917
LS refinement shellResolution: 3→3.078 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.385 399 -
Rwork0.357 7567 -
all-7966 -
obs--100 %

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