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- PDB-2i78: Crystal structure of human dipeptidyl peptidase IV (DPP IV) compl... -

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Basic information

Entry
Database: PDB / ID: 2i78
TitleCrystal structure of human dipeptidyl peptidase IV (DPP IV) complexed with ABT-341, a cyclohexene-constrained phenethylamine inhibitor
ComponentsDipeptidyl peptidase IV
KeywordsHYDROLASE / serine peptidase
Function / homology
Function and homology information


glucagon processing / negative regulation of neutrophil chemotaxis / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / regulation of cell-cell adhesion mediated by integrin / negative regulation of extracellular matrix disassembly / psychomotor behavior / dipeptidyl-peptidase IV / chemorepellent activity / intercellular canaliculus / dipeptidyl-peptidase activity ...glucagon processing / negative regulation of neutrophil chemotaxis / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / regulation of cell-cell adhesion mediated by integrin / negative regulation of extracellular matrix disassembly / psychomotor behavior / dipeptidyl-peptidase IV / chemorepellent activity / intercellular canaliculus / dipeptidyl-peptidase activity / peptide hormone processing / locomotory exploration behavior / lamellipodium membrane / endocytic vesicle / endothelial cell migration / behavioral fear response / aminopeptidase activity / T cell costimulation / serine-type peptidase activity / T cell activation / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / virus receptor activity / lamellipodium / protease binding / receptor-mediated endocytosis of virus by host cell / membrane fusion / receptor-mediated virion attachment to host cell / response to hypoxia / cell adhesion / symbiont entry into host cell / membrane raft / apical plasma membrane / lysosomal membrane / signaling receptor binding / serine-type endopeptidase activity / focal adhesion / positive regulation of cell population proliferation / cell surface / protein homodimerization activity / proteolysis / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane
Similarity search - Function
Dipeptidylpeptidase IV, N-terminal domain / 8 Propeller / Methanol Dehydrogenase; Chain A / Prolyl endopeptidase family serine active site. / Peptidase S9, serine active site / 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, catalytic domain ...Dipeptidylpeptidase IV, N-terminal domain / 8 Propeller / Methanol Dehydrogenase; Chain A / Prolyl endopeptidase family serine active site. / Peptidase S9, serine active site / 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, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-KIQ / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsLongenecker, K.L. / Pei, Z. / Li, X.
CitationJournal: To be Published
Title: Discovery of Cyclohexene-constrained Phenethylamine ABT-341, a Highly Potent, Selective, Orally Bioavailable, Safe and Potential Next-generation Dipeptidyl Peptidase IV Inhibitor for the ...Title: Discovery of Cyclohexene-constrained Phenethylamine ABT-341, a Highly Potent, Selective, Orally Bioavailable, Safe and Potential Next-generation Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes
Authors: Pei, Z. / Li, X. / vonGeldern, T.W. / Madar, D.J. / L Longenecker, K. / Yong, H. / Lubben, T.H. / Stewart, K.D. / Zinker, B.A. / Backes, B.J. / Judd, A.S. / Mulhern, M. / Ballaron, S.J. / ...Authors: Pei, Z. / Li, X. / vonGeldern, T.W. / Madar, D.J. / L Longenecker, K. / Yong, H. / Lubben, T.H. / Stewart, K.D. / Zinker, B.A. / Backes, B.J. / Judd, A.S. / Mulhern, M. / Ballaron, S.J. / Stashko, M.A. / Mika, A.K. / Beno, D.W.A. / Reinhart, G.A. / Fryer, R.M. / Preusser, L.C. / Kempf-Grote, A.J. / Sham, H.L. / Trevillyan, J.M.
History
DepositionAug 30, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Derived calculations / Version format compliance
Revision 1.2Oct 18, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dipeptidyl peptidase IV
B: Dipeptidyl peptidase IV
C: Dipeptidyl peptidase IV
D: Dipeptidyl peptidase IV
hetero molecules


Theoretical massNumber of molelcules
Total (without water)337,4555
Polymers337,0094
Non-polymers4451
Water11,205622
1
A: Dipeptidyl peptidase IV
B: Dipeptidyl peptidase IV
hetero molecules


Theoretical massNumber of molelcules
Total (without water)168,9503
Polymers168,5052
Non-polymers4451
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5070 Å2
ΔGint-17 kcal/mol
Surface area58170 Å2
MethodPISA, PQS
2
C: Dipeptidyl peptidase IV
D: Dipeptidyl peptidase IV


Theoretical massNumber of molelcules
Total (without water)168,5052
Polymers168,5052
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4390 Å2
ΔGint-18 kcal/mol
Surface area58140 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)119.933, 126.419, 127.531
Angle α, β, γ (deg.)90.000, 100.260, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12C
22D

NCS domain segments:

Component-ID: 1 / Beg label comp-ID: SER / End label comp-ID: SER / Refine code: 4 / Auth seq-ID: 39 - 764 / Label seq-ID: 1 - 726

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12CC
22DD

NCS ensembles :
ID
1
2
DetailsA dimer of dpp4 molecules is thought to be biologically relevant, and the asymmetric unit is comprised of two dimers.

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Components

#1: Protein
Dipeptidyl peptidase IV / / Dipeptidyl peptidase 4 / DPP IV / T-cell activation antigen CD26 / TP103 / Adenosine deaminase ...Dipeptidyl peptidase 4 / DPP IV / T-cell activation antigen CD26 / TP103 / Adenosine deaminase complexing protein 2 / ADABP


Mass: 84252.336 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27487, dipeptidyl-peptidase IV
#2: Chemical ChemComp-KIQ / (1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINE


Mass: 445.362 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17F6N5O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 622 / 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: 2.82 Å3/Da / Density % sol: 56.41 %
Crystal growMethod: vapor diffusion / Details: VAPOR DIFFUSION

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 126817 / % possible obs: 98.3 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.078 / Χ2: 1.018 / Net I/σ(I): 9.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.5-2.592.30.389109870.75185.7
2.59-2.693.30.326126260.667198.3
2.69-2.823.50.263127880.687199.4
2.82-2.963.60.193128010.764199.7
2.96-3.153.70.142128800.87199.9
3.15-3.393.80.102128511.0021100
3.39-3.733.90.077129311.2041100
3.73-4.273.90.058129161.3011100
4.27-5.383.90.047129161.4031100
5.38-503.80.038131211.211199.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.2.0005refinement
PDB_EXTRACT2data extraction
HKL-2000data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→129.1 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.876 / SU B: 10.455 / SU ML: 0.232 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.575 / ESU R Free: 0.317 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.275 6375 5 %RANDOM
Rwork0.216 ---
all0.219 ---
obs-126792 98.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.628 Å2
Baniso -1Baniso -2Baniso -3
1--1.27 Å20 Å20.26 Å2
2--0.12 Å20 Å2
3---1.25 Å2
Refinement stepCycle: LAST / Resolution: 2.5→129.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23796 0 31 622 24449
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.02224534
X-RAY DIFFRACTIONr_angle_refined_deg1.3411.93133384
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.84452900
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.88623.9611232
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.838153980
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.03615120
X-RAY DIFFRACTIONr_chiral_restr0.10.23507
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219010
X-RAY DIFFRACTIONr_nbd_refined0.2190.211247
X-RAY DIFFRACTIONr_nbtor_refined0.3120.216549
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1720.21213
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2250.270
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3060.213
X-RAY DIFFRACTIONr_mcbond_it0.5411.514809
X-RAY DIFFRACTIONr_mcangle_it0.96223471
X-RAY DIFFRACTIONr_scbond_it1.118311465
X-RAY DIFFRACTIONr_scangle_it1.7824.59913
Refine LS restraints NCS

Dom-ID: 1 / Number: 5949 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDTypeRms dev position (Å)Weight position
1AMEDIUM POSITIONAL0.310.5
1AMEDIUM THERMAL0.752
2CMEDIUM POSITIONAL0.280.5
2CMEDIUM THERMAL0.542
LS refinement shellResolution: 2.5→2.566 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.389 345 -
Rwork0.339 7246 -
obs-7591 79.94 %

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