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- PDB-3vjl: Crystal structure of human depiptidyl peptidase IV (DPP-4) in com... -

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Basic information

Entry
Database: PDB / ID: 3vjl
TitleCrystal structure of human depiptidyl peptidase IV (DPP-4) in complex with a prolylthiazolidine inhibitor #2
ComponentsDipeptidyl peptidase 4
KeywordsHYDROLASE/HYDROLASE INHIBITOR / ALPHA/BETA / BETA-PROPELLER / AMINOPEPTIDASE / SERINE PROTEASE / SIGNAL-ANCHOR / TRANSMEMBRANE / DIABETES / GLYCOPROTEIN / CELL MEMBRANE / 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 / chemorepellent activity / psychomotor behavior / intercellular canaliculus / 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 / chemorepellent activity / psychomotor behavior / intercellular canaliculus / dipeptidyl-peptidase activity / peptide hormone processing / locomotory exploration behavior / lamellipodium membrane / endocytic vesicle / behavioral fear response / endothelial cell migration / aminopeptidase activity / receptor-mediated endocytosis of virus by host cell / 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 / response to hypoxia / receptor-mediated virion attachment to host cell / cell adhesion / apical plasma membrane / membrane raft / symbiont entry into host cell / signaling receptor binding / lysosomal membrane / serine-type endopeptidase activity / 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 / Prolyl endopeptidase family serine active site. / Peptidase S9, serine active site / : / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / 8 Propeller / Methanol Dehydrogenase; Chain A / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family ...Dipeptidylpeptidase IV, N-terminal domain / Prolyl endopeptidase family serine active site. / Peptidase S9, serine active site / : / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / 8 Propeller / Methanol Dehydrogenase; Chain A / 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-W94 / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.393 Å
AuthorsAkahoshi, F. / Kishida, H. / Miyaguchi, I. / Yoshida, T. / Ishii, S.
CitationJournal: Bioorg.Med.Chem. / Year: 2012
Title: Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): A highly potent, selective, long- ...Title: Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): A highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
Authors: Yoshida, T. / Akahoshi, F. / Sakashita, H. / Kitajima, H. / Nakamura, M. / Sonda, S. / Takeuchi, M. / Tanaka, Y. / Ueda, N. / Sekiguchi, S. / Ishige, T. / Shima, K. / Nabeno, M. / Abe, Y. / ...Authors: Yoshida, T. / Akahoshi, F. / Sakashita, H. / Kitajima, H. / Nakamura, M. / Sonda, S. / Takeuchi, M. / Tanaka, Y. / Ueda, N. / Sekiguchi, S. / Ishige, T. / Shima, K. / Nabeno, M. / Abe, Y. / Anabuki, J. / Soejima, A. / Yoshida, K. / Takashina, Y. / Ishii, S. / Kiuchi, S. / Fukuda, S. / Tsutsumiuchi, R. / Kosaka, K. / Murozono, T. / Nakamaru, Y. / Utsumi, H. / Masutomi, N. / Kishida, H. / Miyaguchi, I. / Hayashi, Y.
History
DepositionOct 24, 2011Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 24, 2012Provider: repository / Type: Initial release
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / 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_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 / _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_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)176,16815
Polymers171,7602
Non-polymers4,40813
Water16,105894
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9030 Å2
ΔGint45 kcal/mol
Surface area59990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)117.810, 125.830, 137.129
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / Dipeptidyl peptidase 4 membrane form / Dipeptidyl peptidase IV membrane form / Dipeptidyl peptidase 4 soluble form / Dipeptidyl peptidase IV soluble form


Mass: 85880.031 Da / Num. of mol.: 2 / Fragment: UNP residues 33-766
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Plasmid: pPSC8 / Cell line (production host): expresSF+ / 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.: 5
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: Chemical ChemComp-W94 / [(2S,4S)-4-{4-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]piperidin-1-yl}pyrrolidin-2-yl](1,3-thiazolidin-3-yl)methanone


Mass: 479.562 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H28F3N5OS
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6
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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 894 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.96 Å3/Da / Density % sol: 58.43 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.8
Details: 20% PEG 4000, 0.18M sodium acetate, 0.18M glycine-sodium hydroxide, pH 8.8, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NW12A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Dec 7, 2006 / Details: mirrors
RadiationMonochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.393→30.387 Å / Num. all: 80861 / Num. obs: 80117 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5 % / Biso Wilson estimate: 37.5 Å2 / Rmerge(I) obs: 0.051 / Net I/σ(I): 20.9
Reflection shellResolution: 2.39→2.48 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.173 / Num. unique all: 7811 / % possible all: 97.9

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
REFMAC5.5.0110refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1J2E

1j2e


Resolution: 2.393→30 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.914 / SU B: 6.134 / SU ML: 0.147 / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / ESU R Free: 0.233 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2297 4025 5 %RANDOM
Rwork0.18402 ---
obs0.18632 76090 99.08 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.877 Å2
Baniso -1Baniso -2Baniso -3
1--0.31 Å20 Å20 Å2
2--0.22 Å20 Å2
3---0.08 Å2
Refinement stepCycle: LAST / Resolution: 2.393→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11942 0 290 894 13126
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.02212610
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3431.95817179
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.08951456
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.51823.981618
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.872151996
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.581560
X-RAY DIFFRACTIONr_chiral_restr0.0860.21837
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219707
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5611.57262
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.098211782
X-RAY DIFFRACTIONr_scbond_it1.62435348
X-RAY DIFFRACTIONr_scangle_it2.7184.55397
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.393→2.455 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.292 264 -
Rwork0.211 5399 -
obs-5399 96.42 %

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