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- PDB-6b1e: The structure of DPP4 in complex with Vildagliptin -

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Basic information

Entry
Database: PDB / ID: 6b1e
TitleThe structure of DPP4 in complex with Vildagliptin
ComponentsDipeptidyl peptidase 4Dipeptidyl peptidase-4
KeywordsHYDROLASE/HYDROLASE Inhibitor / Diabetes / DPP4 inhibitors / covalent inhibitors / HYDROLASE / HYDROLASE-HYDROLASE Inhibitor complex
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-LF7 / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.77 Å
AuthorsScapin, G.
CitationJournal: Endocrinol Diabetes Metab / Year: 2018
Title: A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, ...Title: A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice.
Authors: Berger, J.P. / SinhaRoy, R. / Pocai, A. / Kelly, T.M. / Scapin, G. / Gao, Y.D. / Pryor, K.A.D. / Wu, J.K. / Eiermann, G.J. / Xu, S.S. / Zhang, X. / Tatosian, D.A. / Weber, A.E. / Thornberry, N.A. / Carr, R.D.
History
DepositionSep 18, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 27, 2017Provider: repository / Type: Initial release
Revision 2.0Feb 7, 2018Group: Atomic model / Derived calculations ...Atomic model / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / entity / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _chem_comp.formula / _chem_comp.name / _chem_comp.pdbx_synonyms / _entity.formula_weight / _entity.pdbx_description / _struct_site_gen.auth_seq_id
Revision 2.1Dec 12, 2018Group: Data collection / Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.year
Revision 2.2Mar 13, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 3.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _atom_site_anisotrop.id / _atom_site_anisotrop.pdbx_label_asym_id / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry
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)173,66417
Polymers168,9532
Non-polymers4,71115
Water33,8141877
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9570 Å2
ΔGint45 kcal/mol
Surface area59900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.314, 125.751, 136.865
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 84476.648 Da / Num. of mol.: 2 / Mutation: S39T
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

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Sugars , 2 types, 12 molecules

#2: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 7 / Source method: isolated from a natural source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: isolated from a natural 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

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Non-polymers , 3 types, 1880 molecules

#3: Chemical ChemComp-LF7 / 2-{[(1r,3s,5R,7S)-3-hydroxytricyclo[3.3.1.1~3,7~]decan-1-yl]amino}-1-{(2S)-2-[(E)-iminomethyl]pyrrolidin-1-yl}ethan-1-o ne / Vildagliptin, bound form / Vildagliptin


Mass: 305.415 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H27N3O2 / Comment: inhibitor*YM
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Na
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1877 / 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: 3.01 Å3/Da / Density % sol: 59.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: PEG 4000, SODIUM ACETATE, TRIS, pH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 5, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.77→136.865 Å / Num. all: 197793 / Num. obs: 197793 / % possible obs: 99.9 % / Redundancy: 6.7 % / Rpim(I) all: 0.026 / Rrim(I) all: 0.068 / Rsym value: 0.058 / Net I/av σ(I): 10.3 / Net I/σ(I): 19.5 / Num. measured all: 1327581
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
1.77-1.826.70.4961.596707144670.2210.580.4963.699.9
1.82-1.8770.4071.998827141470.1760.4720.4074.4100
1.87-1.926.90.3192.494928137370.1390.3710.3195.699.9
1.92-1.986.80.2493.191445133880.110.2910.2496.9100
1.98-2.046.60.192485182129740.0870.2260.1928.6100
2.04-2.126.70.1614.783914125460.0720.1890.16110.399.9
2.12-2.26.60.1276.180389121080.0570.1480.12712.899.9
2.2-2.2970.1136.881265116710.0490.1310.11314.799.9
2.29-2.396.90.0938.277724112110.0410.1080.09317.699.9
2.39-2.56.80.0819.373655107710.0360.0950.08119.999.9
2.5-2.646.50.07110.565702101850.0330.0840.07121.799.9
2.64-2.86.60.06112.16397296620.0270.0710.06125.899.9
2.8-2.996.80.05114.16243991250.0220.0590.05131100
2.99-3.236.80.04315.95800185160.0190.050.04336.3100
3.23-3.546.50.03817.75119878210.0170.0440.03841.299.9
3.54-3.966.20.03418.94388071150.0160.040.03444.299.7
3.96-4.576.40.03214059863050.0130.0340.0348.799.8
4.57-5.66.70.02921.63610853660.0120.0330.02950.599.8
5.6-7.926.20.0321.12636242410.0140.0350.0346.599.9
7.92-136.8656.30.02522.31528524370.0110.0290.02552.399.6

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
SCALA3.3.15data scaling
PDB_EXTRACT3.22data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.77→30 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.956 / SU B: 3.944 / SU ML: 0.057 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.096 / ESU R Free: 0.092 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1859 9939 5 %RANDOM
Rwork0.1608 ---
obs0.162 187696 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 65.76 Å2 / Biso mean: 23.644 Å2 / Biso min: 6.15 Å2
Baniso -1Baniso -2Baniso -3
1--0.82 Å20 Å20 Å2
2--0.3 Å20 Å2
3---0.52 Å2
Refinement stepCycle: final / Resolution: 1.77→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11930 0 353 1877 14160
Biso mean--42.61 26.23 -
Num. residues----1456
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.02212781
X-RAY DIFFRACTIONr_angle_refined_deg1.2681.96317452
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.94151484
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.78723.958624
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.26152029
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5071562
X-RAY DIFFRACTIONr_chiral_restr0.090.21898
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0219817
LS refinement shellResolution: 1.771→1.817 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.263 720 -
Rwork0.239 13685 -
all-14405 -
obs--99.72 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.5974-0.002-0.02240.1228-0.05390.29770.01460.01090.0179-0.0008-0.0077-0.00980.00180.018-0.00690.0545-0.01170.0060.0680.00740.061845.2154.79839.402
20.5016-0.04040.10110.1-0.06770.19940.0013-0.0649-0.0449-0.00630.00330.004-0.007-0.0407-0.00460.0403-0.00370.01070.09920.0070.075-10.59960.22931.784
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A39 - 766
2X-RAY DIFFRACTION1L1
3X-RAY DIFFRACTION2B39 - 766
4X-RAY DIFFRACTION2L2

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