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- PDB-7a3g: Crystal structure of DPP8 in complex with a 4-oxo-b-lactam based ... -

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Basic information

Entry
Database: PDB / ID: 7a3g
TitleCrystal structure of DPP8 in complex with a 4-oxo-b-lactam based inhibitor, 91
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
PHOSPHATE ION / Chem-QXQ / Chem-QXT / trimethylamine oxide / Dipeptidyl peptidase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 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
B: Dipeptidyl peptidase 8
A: Dipeptidyl peptidase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)210,09624
Polymers206,9672
Non-polymers3,12922
Water18010
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7370 Å2
ΔGint-72 kcal/mol
Surface area64740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)153.598, 153.598, 270.222
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61

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Components

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Protein , 1 types, 2 molecules BA

#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.: 2
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

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Non-polymers , 7 types, 32 molecules

#2: Chemical
ChemComp-TMO / trimethylamine oxide / Trimethylamine N-oxide


Mass: 75.110 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H9NO
#3: Chemical ChemComp-QXQ / ~{N}-[3-(7,8-dihydro-5~{H}-[1,3]dioxolo[4,5-g]isoquinolin-6-ylmethyl)phenyl]-2-ethyl-2-methanoyl-butanamide


Mass: 408.490 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H28N2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: PO4
#6: Chemical ChemComp-QXT / 1-[3-(7,8-dihydro-5~{H}-[1,3]dioxolo[4,5-g]isoquinolin-6-ylmethyl)phenyl]-3,3-diethyl-azetidine-2,4-dione


Mass: 406.474 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H26N2O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 4.45 Å3/Da / Density % sol: 72.33 %
Crystal growTemperature: 273 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: Feb 12, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→49.43 Å / Num. obs: 88413 / % possible obs: 100 % / Redundancy: 13.177 % / Biso Wilson estimate: 78.124 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.091 / Rrim(I) all: 0.095 / Χ2: 1.077 / Net I/σ(I): 19.17 / Num. measured all: 1165051 / Scaling rejects: 125
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
2.8-2.8713.6451.5462.0488938652065180.7921.606100
2.87-2.9513.5551.1222.7885342629962960.871.166100
2.95-3.0413.4990.7793.9387485648264810.940.81100
3.04-3.1413.3810.5785.1286618647564730.9610.601100
3.14-3.2613.2330.4027.1183620631963190.980.418100
3.26-3.3912.9960.2749.6282059631463140.990.285100
3.39-3.5512.2320.19412.3978822644464440.9940.202100
3.55-3.7412.3960.15515.4178290631663160.9950.162100
3.74-3.9813.2380.1220.2183852633463340.9970.124100
3.98-4.2913.8330.08227.0286661626562650.9990.085100
4.29-4.7413.630.06334.0585417626762670.9990.065100
4.74-5.4413.3530.05736.9783245623462340.9990.059100
5.44-6.6312.6060.05437.3668654544654460.9990.057100
6.63-8.412.2910.04245.741813340234020.9990.044100
8.4-10.7913.6880.03263.16238581743174310.033100
10.79-15.7413.3620.02972.15142971071107010.0399.9
15.74-25.212.6660.02772.17485138438310.02899.7
25.2-49.4311.380.02668.4312291261080.9990.02785.7

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Processing

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

6eop


Resolution: 2.8→49.43 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.93 / SU B: 13.832 / SU ML: 0.253 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.406 / ESU R Free: 0.278
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2423 4421 5 %RANDOM
Rwork0.209 ---
obs0.2107 83992 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 197.22 Å2 / Biso mean: 89.573 Å2 / Biso min: 58.23 Å2
Baniso -1Baniso -2Baniso -3
1-2.07 Å21.03 Å20 Å2
2--2.07 Å2-0 Å2
3----6.7 Å2
Refinement stepCycle: final / Resolution: 2.8→49.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13435 0 206 10 13651
Biso mean--116.06 78.39 -
Num. residues----1655
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01914018
X-RAY DIFFRACTIONr_bond_other_d0.0020.0212993
X-RAY DIFFRACTIONr_angle_refined_deg1.3651.97119038
X-RAY DIFFRACTIONr_angle_other_deg0.866329960
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.08551651
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.62923.536673
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.126152309
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.9661588
X-RAY DIFFRACTIONr_chiral_restr0.0720.22001
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02115636
X-RAY DIFFRACTIONr_gen_planes_other0.0010.023314
LS refinement shellResolution: 2.8→2.872 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 324 -
Rwork0.378 6151 -
all-6475 -
obs--99.97 %

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