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- PDB-3o95: Crystal Structure of Human DPP4 Bound to TAK-100 -

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Basic information

Entry
Database: PDB / ID: 3o95
TitleCrystal Structure of Human DPP4 Bound to TAK-100
ComponentsDipeptidyl peptidase 4Dipeptidyl peptidase-4
KeywordsHYDROLASE / SIGNALING PROTEIN/INHIBITOR / protease and 8-bladed beta-propeller domain / Aminopeptidase / Cell membrane / Glycoprotein / Membrane / Protease / Secreted / Serine protease / Signal-anchor / Transmembrane / SIGNALING PROTEIN / SIGNALING PROTEIN-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
triacetyl-beta-chitotriose / Chem-01T / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.85 Å
AuthorsYano, J.K. / Aertgeerts, K.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Discovery of a 3-Pyridylacetic Acid Derivative (TAK-100) as a Potent, Selective and Orally Active Dipeptidyl Peptidase IV (DPP-4) Inhibitor.
Authors: Miyamoto, Y. / Banno, Y. / Yamashita, T. / Fujimoto, T. / Oi, S. / Moritoh, Y. / Asakawa, T. / Kataoka, O. / Yashiro, H. / Takeuchi, K. / Suzuki, N. / Ikedo, K. / Kosaka, T. / Tsubotani, S. ...Authors: Miyamoto, Y. / Banno, Y. / Yamashita, T. / Fujimoto, T. / Oi, S. / Moritoh, Y. / Asakawa, T. / Kataoka, O. / Yashiro, H. / Takeuchi, K. / Suzuki, N. / Ikedo, K. / Kosaka, T. / Tsubotani, S. / Tani, A. / Sasaki, M. / Funami, M. / Amano, M. / Yamamoto, Y. / Aertgeerts, K. / Yano, J. / Maezaki, H.
History
DepositionAug 3, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 26, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 8, 2014Group: Database references
Revision 1.3Nov 8, 2017Group: Refinement description / Category: software
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_PDB_caveat / entity / entity_name_com / 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_molecule_features / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_validate_chiral / struct_asym / struct_conn / struct_ref_seq_dif / 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 / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_chiral.auth_asym_id / _pdbx_validate_chiral.auth_seq_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.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _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
C: Dipeptidyl peptidase 4
D: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)350,77528
Polymers343,1044
Non-polymers7,67124
Water8,773487
1
A: Dipeptidyl peptidase 4
B: Dipeptidyl peptidase 4
hetero molecules

C: Dipeptidyl peptidase 4
D: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)350,77528
Polymers343,1044
Non-polymers7,67124
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_646-x+1,y-1/2,-z+11
Buried area16710 Å2
ΔGint63 kcal/mol
Surface area118540 Å2
MethodPISA
2
A: Dipeptidyl peptidase 4
B: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,91315
Polymers171,5522
Non-polymers4,36113
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8650 Å2
ΔGint36 kcal/mol
Surface area59960 Å2
MethodPISA
3
C: Dipeptidyl peptidase 4
D: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)174,86113
Polymers171,5522
Non-polymers3,30911
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7440 Å2
ΔGint26 kcal/mol
Surface area59210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.718, 123.335, 144.419
Angle α, β, γ (deg.)90.00, 114.78, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#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 / ADCP-2 / ADABP


Mass: 85775.945 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADCP2, CD26, DPP4 / Plasmid: pFASTBAC / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27487, dipeptidyl-peptidase IV

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Sugars , 3 types, 20 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 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: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose / triacetyl-beta-chitotriose


Type: oligosaccharide, Oligosaccharide / Class: Inhibitor / Mass: 627.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide / References: triacetyl-beta-chitotriose
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,3,2/[a2122h-1b_1-5_2*NCC/3=O]/1-1-1/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(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.: 12
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

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Non-polymers , 2 types, 491 molecules

#5: Chemical
ChemComp-01T / [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid / TAK-100


Mass: 354.486 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H30N2O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 487 / 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: 2.87 Å3/Da / Density % sol: 57.12 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 20% PEG MME 2000, 100 mM Bicine, pH 8-8.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K
PH range: 8-8.5

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Data collection

DiffractionMean temperature: 92 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 14, 2007
RadiationMonochromator: Si (220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.85→50 Å / Num. obs: 89585 / % possible obs: 99.3 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.106 / Χ2: 1.001 / Net I/σ(I): 7.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.85-2.92.90.5145810.991192.4
2.9-2.9630.47348601.013196.6
2.96-3.033.20.448970.985199
3.03-3.13.30.34849901.017199.8
3.1-3.183.30.28849761.0051100
3.18-3.263.30.24249971.0011100
3.26-3.363.30.20449920.9951100
3.36-3.473.30.16250060.9961100
3.47-3.593.30.13749921.0021100
3.59-3.733.30.12149800.9981100
3.73-3.93.30.10850171.0131100
3.9-4.113.30.09550200.9921100
4.11-4.373.30.08449951.003199.9
4.37-4.73.30.07350001.03199.9
4.7-5.183.20.06550300.9921100
5.18-5.933.20.06250560.9781100
5.93-7.463.40.05950451.0031100
7.46-503.30.03251510.995199.9

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.13 Å48.21 Å
Translation3.13 Å48.21 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMAC5.2.0019refinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.85→35 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.89 / Occupancy max: 1 / Occupancy min: 1 / SU B: 30.208 / SU ML: 0.298 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.391 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2485 4489 5 %RANDOM
Rwork0.187 ---
obs0.1901 89524 99.19 %-
all-90249 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 97.81 Å2 / Biso mean: 49.0607 Å2 / Biso min: 4.81 Å2
Baniso -1Baniso -2Baniso -3
1--2.81 Å20 Å2-0.43 Å2
2--1.8 Å20 Å2
3---0.65 Å2
Refinement stepCycle: LAST / Resolution: 2.85→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23873 0 510 487 24870
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.02225129
X-RAY DIFFRACTIONr_angle_refined_deg1.2371.95334227
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.40452909
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.09523.9561236
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.31153987
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.97515119
X-RAY DIFFRACTIONr_chiral_restr0.0850.23646
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219249
X-RAY DIFFRACTIONr_nbd_refined0.2090.212445
X-RAY DIFFRACTIONr_nbtor_refined0.3170.217064
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1460.21225
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1990.258
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1050.212
X-RAY DIFFRACTIONr_mcbond_it0.3481.514783
X-RAY DIFFRACTIONr_mcangle_it0.629223540
X-RAY DIFFRACTIONr_scbond_it0.884312056
X-RAY DIFFRACTIONr_scangle_it1.5274.510687
LS refinement shellResolution: 2.853→2.927 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 300 -
Rwork0.276 5773 -
all-6073 -
obs--91.57 %

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