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- PDB-2i03: Crystal structure of human dipeptidyl peptidase 4 (DPP IV) with p... -

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Basic information

Entry
Database: PDB / ID: 2i03
TitleCrystal structure of human dipeptidyl peptidase 4 (DPP IV) with potent alkynyl cyanopyrrolidine (ABT-279)
ComponentsDipeptidyl peptidase 4Dipeptidyl peptidase-4
KeywordsHYDROLASE / enzyme / 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 / dipeptidyl-peptidase IV / psychomotor behavior / 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 / dipeptidyl-peptidase IV / psychomotor behavior / 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-AXD / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsLongenecker, K.L. / Madar, D.J.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well- ...Title: Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.
Authors: Madar, D.J. / Kopecka, H. / Pireh, D. / Yong, H. / Pei, Z. / Li, X. / Wiedeman, P.E. / Djuric, S.W. / Von Geldern, T.W. / Fickes, M.G. / Bhagavatula, L. / McDermott, T. / Wittenberger, S. / ...Authors: Madar, D.J. / Kopecka, H. / Pireh, D. / Yong, H. / Pei, Z. / Li, X. / Wiedeman, P.E. / Djuric, S.W. / Von Geldern, T.W. / Fickes, M.G. / Bhagavatula, L. / McDermott, T. / Wittenberger, S. / Richards, S.J. / Longenecker, K.L. / Stewart, K.D. / Lubben, T.H. / Ballaron, S.J. / Stashko, M.A. / Long, M.A. / Wells, H. / Zinker, B.A. / Mika, A.K. / Beno, D.W. / Kempf-Grote, A.J. / Polakowski, J. / Segreti, J. / Reinhart, G.A. / Fryer, R.M. / Sham, H.L. / Trevillyan, J.M.
History
DepositionAug 9, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 12, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dipeptidyl peptidase 4
B: Dipeptidyl peptidase 4
C: Dipeptidyl peptidase 4
D: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)337,4095
Polymers337,0094
Non-polymers3991
Water53,2702957
1
A: Dipeptidyl peptidase 4
B: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)168,9043
Polymers168,5052
Non-polymers3991
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5060 Å2
ΔGint-21 kcal/mol
Surface area57220 Å2
MethodPISA
2
C: Dipeptidyl peptidase 4
D: Dipeptidyl peptidase 4


Theoretical massNumber of molelcules
Total (without water)168,5052
Polymers168,5052
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4380 Å2
ΔGint-18 kcal/mol
Surface area57450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.252, 126.994, 127.257
Angle α, β, γ (deg.)90.000, 96.560, 90.000
Int Tables number4
Space group name H-MP1211
Detailsbiologically relevant unit is one dimer, and the asymmetric unit is composed of two dimers.

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Components

#1: Protein
Dipeptidyl peptidase 4 / Dipeptidyl peptidase-4 / Dipeptidyl peptidase IV / DPP IV / T-cell activation antigen CD26 / TP103 / Adenosine deaminase ...Dipeptidyl peptidase IV / 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-AXD / 2-[4-({2-[(2S,5R)-2-(AMINOMETHYL)-5-ETHYNYLPYRROLIDIN-1-YL]-2-OXOETHYL}AMINO)-4-METHYLPIPERIDIN-1-YL]ISONICOTINIC ACID


Mass: 399.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H29N5O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2957 / 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: 2.86 Å3/Da / Density % sol: 57.05 %
Crystal growMethod: vapor diffusion / Details: VAPOR DIFFUSION

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 143995 / % possible obs: 97.3 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.116 / Χ2: 1.068 / Net I/σ(I): 5.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.4-2.493.30.452140990.3495.9
2.49-2.593.40.392141230.38395.9
2.59-2.73.40.321142030.4796.1
2.7-2.853.40.255142140.52696.4
2.85-3.023.30.204143380.70696.9
3.02-3.263.30.165143560.98297.3
3.26-3.583.30.134145001.37298.1
3.58-4.13.30.108146851.72199
4.1-5.173.40.085147031.97599.1
5.17-503.30.077147742.12498.1

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT2data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→20 Å / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.245 7166 4.8 %
Rwork0.179 --
obs-143412 96.9 %
Displacement parametersBiso mean: 50.579 Å2
Baniso -1Baniso -2Baniso -3
1-13.519 Å20 Å2-1.157 Å2
2--4.244 Å20 Å2
3----17.762 Å2
Refinement stepCycle: LAST / Resolution: 2.4→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23796 0 29 2957 26782
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_repADD.param
X-RAY DIFFRACTION2water_rep.param
X-RAY DIFFRACTION3add.param

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