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- PDB-2rgu: Crystal structure of complex of human DPP4 and inhibitor -

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Basic information

Entry
Database: PDB / ID: 2rgu
TitleCrystal structure of complex of human DPP4 and inhibitor
ComponentsDipeptidyl peptidase 4Dipeptidyl peptidase-4
KeywordsHYDROLASE / peptidase / inhibitor / Aminopeptidase / Glycoprotein / Membrane / Protease / Secreted / Serine protease / Signal-anchor / Transmembrane
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 / intercellular canaliculus / chemorepellent activity / 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 / intercellular canaliculus / chemorepellent activity / dipeptidyl-peptidase activity / peptide hormone processing / locomotory exploration behavior / lamellipodium membrane / endocytic vesicle / endothelial cell migration / behavioral fear response / aminopeptidase activity / T cell costimulation / T cell activation / serine-type peptidase activity / 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-356 / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.6 Å
AuthorsNar, H. / Himmelsbach, F. / Eckhardt, M.
CitationJournal: J.Med.Chem. / Year: 2007
Title: 8-(3-(R)-Aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a Highly Potent, Selective, Long-Acting, and Orally Bioavailable ...Title: 8-(3-(R)-Aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a Highly Potent, Selective, Long-Acting, and Orally Bioavailable DPP-4 Inhibitor for the Treatment of Type 2 Diabetes.
Authors: Eckhardt, M. / Langkopf, E. / Mark, M. / Tadayyon, M. / Thomas, L. / Nar, H. / Pfrengle, W. / Guth, B. / Lotz, R. / Sieger, P. / Fuchs, H. / Himmelsbach, F.
History
DepositionOct 5, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.2Apr 6, 2016Group: Non-polymer description
Revision 1.3Oct 25, 2017Group: Refinement description / Category: software
Revision 1.4Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,29812
Polymers170,5832
Non-polymers2,71510
Water3,729207
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.300, 67.100, 419.900
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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 (Contains: Dipeptidyl peptidase 4 membrane form / Dipeptidyl peptidase 4 soluble form)


Mass: 85291.508 Da / Num. of mol.: 2 / Fragment: Extracellular domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Production host: Pichia pastoris (fungus) / Strain (production host): KM71H (Muts) / References: UniProt: P27487, dipeptidyl-peptidase IV
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-356 / 8-[(3R)-3-Aminopiperidin-1-yl]-7-but-2-yn-1-yl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-d ione / Linagliptin / Linagliptin


Mass: 472.542 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H28N8O2 / Comment: medication*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 207 / 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: 2.72 Å3/Da / Density % sol: 54.83 %
Crystal growMethod: vapor diffusion, hanging drop
Details: 25% PEG 3350, 150mM MgCl2, Tris-HCl pH 8.1, 15% Glycerol, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9793 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Oct 3, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.6→40 Å / Num. obs: 56898 / % possible obs: 97.5 % / Rmerge(I) obs: 0.104 / Χ2: 1.042 / Net I/σ(I): 11.6
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.6-2.690.38655791.04197.5
2.69-2.80.30956531.084198.8
2.8-2.930.25757621.153199.7
2.93-3.080.20356791.23199.5
3.08-3.280.15857291.23199.4
3.28-3.530.13157651.215199.1
3.53-3.880.1157421.093198.8
3.88-4.440.08855960.915195.4
4.44-5.60.07855470.724193.5
5.6-400.07158460.608193.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3data extraction
MAR345CCDdata collection
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.6→40 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflection
Rfree0.276 2874 4.9 %
Rwork0.217 --
obs-56750 97.5 %
Displacement parametersBiso mean: 53.82 Å2
Baniso -1Baniso -2Baniso -3
1--2.447 Å20 Å20 Å2
2---18.55 Å20 Å2
3---20.997 Å2
Refinement stepCycle: LAST / Resolution: 2.6→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11926 0 190 207 12323
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.424
X-RAY DIFFRACTIONc_mcbond_it0.8990.75
X-RAY DIFFRACTIONc_scbond_it1.1151
X-RAY DIFFRACTIONc_mcangle_it1.5981
X-RAY DIFFRACTIONc_scangle_it1.7791.25
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1MSI_CNX_TOPPAR:protein_rep.paramMSI_CNX_TOPPAR:protein.top
X-RAY DIFFRACTION2MSI_CNX_TOPPAR:dna-rna_rep.paramMSI_CNX_TOPPAR:dna-rna.top
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.paramMSI_CNX_TOPPAR:water.top
X-RAY DIFFRACTION4MSI_CNX_TOPPAR:ion.paramMSI_CNX_TOPPAR:ion.top
X-RAY DIFFRACTION5inhi.parinhi.top

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