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- PDB-6b1o: The structure of DPP4 in complex with Vildagliptin Analog -

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Basic information

Entry
Database: PDB / ID: 6b1o
TitleThe structure of DPP4 in complex with Vildagliptin Analog
ComponentsDipeptidyl 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 / regulation of cell-cell adhesion mediated by integrin / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / intercellular canaliculus / psychomotor behavior / chemorepellent activity / dipeptidyl-peptidase activity ...glucagon processing / negative regulation of neutrophil chemotaxis / regulation of cell-cell adhesion mediated by integrin / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / intercellular canaliculus / psychomotor behavior / chemorepellent activity / dipeptidyl-peptidase activity / peptide hormone processing / locomotory exploration behavior / lamellipodium membrane / endocytic vesicle / behavioral fear response / endothelial cell migration / aminopeptidase activity / T cell costimulation / serine-type peptidase activity / T cell activation / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / lamellipodium / virus receptor activity / protease binding / membrane fusion / receptor-mediated endocytosis of virus by host cell / receptor-mediated virion attachment to host cell / response to hypoxia / cell adhesion / symbiont entry into host cell / membrane raft / apical plasma membrane / lysosomal membrane / serine-type endopeptidase activity / signaling receptor binding / focal adhesion / positive regulation of cell population proliferation / cell surface / protein homodimerization activity / proteolysis / extracellular exosome / extracellular region / identical protein binding / membrane / 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 ...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-C8S / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.91 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 1.1Dec 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 1.2Mar 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 2.0Jul 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 / 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 / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)174,10716
Polymers168,9532
Non-polymers5,15414
Water27,6891537
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9910 Å2
ΔGint59 kcal/mol
Surface area60720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)119.515, 123.342, 130.958
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 / 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
#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.: 9
Source method: isolated from a genetically manipulated 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
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3
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
#4: Chemical ChemComp-C8S / (2S)-2-amino-1-[(1S,3S,5S)-3-(aminomethyl)-2-azabicyclo[3.1.0]hexan-2-yl]-2-[(1r,3R,5S,7S)-3,5-dihydroxytricyclo[3.3.1.1~3,7~]decan-1-yl]ethan-1-one


Mass: 335.441 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C18H29N3O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1537 / 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: 56.94 %
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: Feb 11, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.91→130.958 Å / Num. all: 150961 / Num. obs: 150961 / % possible obs: 100 % / Redundancy: 6.5 % / Rpim(I) all: 0.037 / Rrim(I) all: 0.095 / Rsym value: 0.079 / Net I/av σ(I): 6.8 / Net I/σ(I): 14.8 / Num. measured all: 985727
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
1.91-1.966.50.4891.572258110590.2310.5890.4893.3100
1.96-2.016.50.374269979107360.1790.4550.3744.3100
2.01-2.076.90.32.472243105130.1390.3610.35.5100
2.07-2.136.80.2552.969422101810.1170.3040.2556.5100
2.13-2.26.70.2033.66655799020.0940.2440.2038.1100
2.2-2.286.50.1846251695670.0850.2160.189100
2.28-2.366.50.154.85988392390.070.1790.1510.6100
2.36-2.466.50.1315.55786589180.0620.1590.13112.1100
2.46-2.576.80.1166.25876485940.0530.1380.11614.1100
2.57-2.76.80.1036.95511181380.0470.1230.10316100
2.7-2.846.60.0927.75175678100.0430.1090.09218.1100
2.84-3.016.20.088.64602073870.0390.0980.0820.499.9
3.01-3.226.30.0719.54346369530.0350.0880.07123.399.9
3.22-3.486.50.06510.44227764820.0310.0790.06526.6100
3.48-3.816.30.06113786259850.0290.0730.0628.599.9
3.81-4.265.90.05611.43225154380.0270.0680.0562999.8
4.26-4.926.10.05212.12928948310.0250.0630.05230.899.9
4.92-6.036.50.04912.92676141040.0220.0570.04931.799.9
6.03-8.526.20.04513.92000332500.0210.0530.0453199.9
8.52-130.9586.10.03815.71144718740.0170.0440.03832.799.7

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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: 1.91→30 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.946 / SU B: 5.887 / SU ML: 0.078 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.133 / ESU R Free: 0.122 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2015 7621 5.1 %RANDOM
Rwork0.1717 ---
obs0.1732 143198 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 73.59 Å2 / Biso mean: 26.993 Å2 / Biso min: 11.67 Å2
Baniso -1Baniso -2Baniso -3
1--0.86 Å20 Å20 Å2
2---0.13 Å20 Å2
3---1 Å2
Refinement stepCycle: final / Resolution: 1.91→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11930 0 342 1537 13809
Biso mean--47.58 30.93 -
Num. residues----1456
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.02212746
X-RAY DIFFRACTIONr_angle_refined_deg1.2441.96417395
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.05351460
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.22723.981628
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.49152017
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5361562
X-RAY DIFFRACTIONr_chiral_restr0.0890.21889
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219766
LS refinement shellResolution: 1.906→1.955 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.273 550 -
Rwork0.241 10449 -
all-10999 -
obs--99.83 %
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)
10.5407-0.0262-0.0610.19750.08310.21960.005-0.03810.0445-0.0456-0.0087-0.0010.00990.03310.00370.02450.0054-0.00420.01470.00340.010510.4644.64429.965
20.47760.01910.00710.19980.05950.24960.0125-0.0140.0267-0.0057-0.00120.00680.0162-0.0371-0.01130.0158-0.0058-0.01010.00970.00070.0111-45.5468.37235.268
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A39 - 766
2X-RAY DIFFRACTION1A811
3X-RAY DIFFRACTION2B39 - 766
4X-RAY DIFFRACTION2B812

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