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- PDB-3q0t: Crystal structure of human dpp-iv in complex withsa-(+)- methyl2-... -

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Entry
Database: PDB / ID: 3q0t
TitleCrystal structure of human dpp-iv in complex withsa-(+)- methyl2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl- 7-oxo-5h-pyrrolo[3,4-b]pyridin-6(7h)-yl)acetate
ComponentsDipeptidyl peptidase 4Dipeptidyl peptidase-4
Keywordshydrolase/hydrolase inhibitor / EXOPEPTIDASE / ALPHA/BETA HYDROLASE FOLD / BETA BARREL / BETA PROPELLER / AMINOPEPTIDASE / GLYCOPROTEIN / MEMBRANE / SERINE PROTEASE / SIGNAL-ANCHOR / TRANSMEMBRANE / 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 / 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-LGE / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.401 Å
AuthorsKlei, H.E.
CitationJournal: To be Published
Title: Discovery of 7-oxo-pyrrolopyridines as potent and selective inhibitors of dpp4
Authors: Wang, W. / Devasthale, P. / Wang, A. / Egan, D. / Morgan, N. / Cap, M. / Fura, A. / Klei, H.E. / Kish, K. / Sun, L. / Levesque, P. / Zahler, R. / Kirby, M. / Hamann, L.G.
History
DepositionDec 16, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 29, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2013Group: Non-polymer description
Revision 1.2Nov 8, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software / Item: _pdbx_unobs_or_zero_occ_atoms.label_asym_id
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 / 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 / _database_PDB_caveat.text / _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_seq_id / _struct_conn.ptnr1_label_asym_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 2.1Sep 13, 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

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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)178,75116
Polymers174,9022
Non-polymers3,84914
Water7,764431
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8240 Å2
ΔGint42 kcal/mol
Surface area58450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.686, 67.569, 420.978
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 / 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: 87450.844 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Plasmid: pPICZalpha / Production host: Pichia pastoris (fungus) / 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.: 2
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 / 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 10
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-LGE / methyl [3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]acetate


Mass: 394.252 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17Cl2N3O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 431 / 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: 2.67 Å3/Da / Density % sol: 53.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: CRYSTALS GROWN IN 2 UL EQUIVOLUME MIXTURE OF PROTEIN SOLUTION (0.1 M NACL, 20 MM TRIS-HCL BUFFER PH 7.8, 9.8 MG/ML PROTEIN) AND CRYSTALLIZATION SOLUTION (17% W/V PEG 3350, 15% W/V GLYCEROL, ...Details: CRYSTALS GROWN IN 2 UL EQUIVOLUME MIXTURE OF PROTEIN SOLUTION (0.1 M NACL, 20 MM TRIS-HCL BUFFER PH 7.8, 9.8 MG/ML PROTEIN) AND CRYSTALLIZATION SOLUTION (17% W/V PEG 3350, 15% W/V GLYCEROL, 200 MM MGCL2, 100 MM TRIS-HCL BUFFER PH 8.5). SUFFICIENT. 100 MM LIGAND STOCK SOLUTION (NEAT DMSO) ADDED TO ACHIEVE 1 MM LIGAND CONCENTRATION. SOAKED OVERNIGHT. HARVESTED DIRECTLY AND CRYO-STORED IN LN2. 2. temperature 298K, VAPOR DIFFUSION, HANGING DROP

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 71882 / % possible obs: 96.1 % / Redundancy: 7.3 % / Rmerge(I) obs: 0.068 / Χ2: 0.938 / Net I/σ(I): 10.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.4-2.495.40.44155760.853175.9
2.49-2.595.80.41266170.86189.9
2.59-2.770.35571810.886197.2
2.7-2.857.70.27773500.887199.4
2.85-3.027.90.1873310.925199.6
3.02-3.2680.11474060.959199.7
3.26-3.587.90.07174250.992199.8
3.58-4.17.80.04975270.985199.8
4.1-5.177.80.0475601.05199.9
5.17-507.40.02979090.9199.4

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIXdev_606refinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NOX

3nox


Resolution: 2.401→47.952 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.34 / σ(F): 1.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2604 2935 4.09 %
Rwork0.2023 --
obs0.2046 71776 96.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 42.697 Å2 / ksol: 0.324 e/Å3
Displacement parametersBiso max: 94.99 Å2 / Biso mean: 44.3494 Å2 / Biso min: 19.11 Å2
Baniso -1Baniso -2Baniso -3
1-3.0123 Å20 Å2-0 Å2
2--13.2554 Å2-0 Å2
3----16.2677 Å2
Refinement stepCycle: LAST / Resolution: 2.401→47.952 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11788 0 248 431 12467
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00812407
X-RAY DIFFRACTIONf_angle_d1.11416901
X-RAY DIFFRACTIONf_chiral_restr0.0751811
X-RAY DIFFRACTIONf_plane_restr0.0042126
X-RAY DIFFRACTIONf_dihedral_angle_d17.0524447
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 21

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4013-2.44060.33781050.28562379248471
2.4406-2.48270.38151180.29322657277579
2.4827-2.52790.37641420.29152933307588
2.5279-2.57650.38781220.30043027314991
2.5765-2.62910.36191270.2723259338695
2.6291-2.68620.37941330.26273259339298
2.6862-2.74870.3331250.2543361348699
2.7487-2.81750.34241630.25023336349999
2.8175-2.89360.30841500.22783330348099
2.8936-2.97880.32671330.222233903523100
2.9788-3.07490.28991450.229233863531100
3.0749-3.18480.28231310.221633663497100
3.1848-3.31230.25151520.210533743526100
3.3123-3.4630.30261280.209934333561100
3.463-3.64550.24631600.198433883548100
3.6455-3.87380.25011510.192534233574100
3.8738-4.17270.23211500.166534193569100
4.1727-4.59230.18631440.149334363580100
4.5923-5.25610.1941420.144534953637100
5.2561-6.61940.24091460.191435273673100
6.6194-47.96120.22191680.19853663383199

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