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- PDB-4a5s: CRYSTAL STRUCTURE OF HUMAN DPP4 IN COMPLEX WITH A NOVAL HETEROCYC... -

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Basic information

Entry
Database: PDB / ID: 4a5s
TitleCRYSTAL STRUCTURE OF HUMAN DPP4 IN COMPLEX WITH A NOVAL HETEROCYCLIC DPP4 INHIBITOR
ComponentsDIPEPTIDYL PEPTIDASE 4 SOLUBLE FORM
KeywordsHYDROLASE / TYPE 2 DIABETES / NOVARTIS COMPOUND NVP-BIV988
Function / homology
Function and homology information


glucagon processing / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / negative regulation of neutrophil chemotaxis / regulation of cell-cell adhesion mediated by integrin / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / psychomotor behavior / intercellular canaliculus / chemorepellent activity / dipeptidyl-peptidase activity ...glucagon processing / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / negative regulation of neutrophil chemotaxis / regulation of cell-cell adhesion mediated by integrin / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / psychomotor behavior / 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 / 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-N7F / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsOstermann, N. / Kroemer, M. / Zink, F. / Gerhartz, B. / Sutton, J.M. / Clark, D.E. / Dunsdon, S.J. / Fenton, G. / Fillmore, A. / Harris, N.V. ...Ostermann, N. / Kroemer, M. / Zink, F. / Gerhartz, B. / Sutton, J.M. / Clark, D.E. / Dunsdon, S.J. / Fenton, G. / Fillmore, A. / Harris, N.V. / Higgs, C. / Hurley, C.A. / Krintel, S.L. / MacKenzie, R.E. / Duttaroy, A. / Gangl, E. / Maniara, W. / Sedrani, R. / Namoto, K. / Sirockin, F. / Trappe, J. / Hassiepen, U. / Baeschlin, D.K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Novel Heterocyclic Dpp-4 Inhibitors for the Treatment of Type 2 Diabetes.
Authors: Sutton, J.M. / Clark, D.E. / Dunsdon, S.J. / Fenton, G. / Fillmore, A. / Harris, N.V. / Higgs, C. / Hurley, C.A. / Krintel, S.L. / Mackenzie, R.E. / Duttaroy, A. / Gangl, E. / Maniara, W. / ...Authors: Sutton, J.M. / Clark, D.E. / Dunsdon, S.J. / Fenton, G. / Fillmore, A. / Harris, N.V. / Higgs, C. / Hurley, C.A. / Krintel, S.L. / Mackenzie, R.E. / Duttaroy, A. / Gangl, E. / Maniara, W. / Sedrani, R. / Namoto, K. / Ostermann, N. / Gerhartz, B. / Sirockin, F. / Trappe, J. / Hassiepen, U. / Baeschlin, D.K.
History
DepositionOct 28, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 8, 2012Provider: repository / Type: Initial release
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Other / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_database_status / 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 / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.src_method / _entity.type / _pdbx_database_status.status_code_sf / _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_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_comp_id
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 SOLUBLE FORM
B: DIPEPTIDYL PEPTIDASE 4 SOLUBLE FORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)176,78323
Polymers171,6622
Non-polymers5,12121
Water28,6441590
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10090 Å2
ΔGint-24.7 kcal/mol
Surface area60290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.183, 121.424, 190.699
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 SOLUBLE FORM / DIPEPTIDYL PEPTIDASE IV SOLUBLE FORM / DIPEPTIDYL PEPTIDASE 4 / ADABP / ADENOSINE DEAMINASE ...DIPEPTIDYL PEPTIDASE IV SOLUBLE FORM / DIPEPTIDYL PEPTIDASE 4 / ADABP / ADENOSINE DEAMINASE COMPLEXING PROTEIN 2 / ADCP-2 / DIPEPTIDYL PEPTIDASE IV / DPP IV / T-CELL ACTIVATION ANTIGEN CD26 / TP103 / CD_ANTIGEN=CD26


Mass: 85831.156 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P27487, dipeptidyl-peptidase IV

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Sugars , 2 types, 13 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpa1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1a_1-5]/1-1-2-2-2/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}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 , 3 types, 1598 molecules

#3: Chemical ChemComp-N7F / 6-[(3S)-3-AMINOPIPERIDIN-1-YL]-5-BENZYL-4-OXO-3-(QUINOLIN-4-YLMETHYL)-4,5-DIHYDRO-3H-PYRROLO[3,2-D]PYRIMIDINE-7-CARBONITRILE


Mass: 489.571 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H27N7O
#5: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1590 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsS437I SEQUENCE CONFLICT KNOWN IN UNIPROT.

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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: 3.28 Å3/Da / Density % sol: 58.2 % / Description: NONE
Crystal growDetails: 2 UL PROTEIN, 0.4 UL RESERVOIR, 0.25 UL WATER; PROTEIN SOLUTION: 5.2 MG/ML DPP4, 25 MM TRIS PH 8, 25 MM NACL, 2 MM NVP-BIV988-AA-1, 2% DMSO; RESERVOIR SOLUTION: 40% PEG 1000, 200 MM TRIS PH ...Details: 2 UL PROTEIN, 0.4 UL RESERVOIR, 0.25 UL WATER; PROTEIN SOLUTION: 5.2 MG/ML DPP4, 25 MM TRIS PH 8, 25 MM NACL, 2 MM NVP-BIV988-AA-1, 2% DMSO; RESERVOIR SOLUTION: 40% PEG 1000, 200 MM TRIS PH 9.0, 200 MM AMMONIUM SULFATE, 5% GLYCEROL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00054
DetectorType: MARRESEARCH / Detector: CCD / Date: Dec 1, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00054 Å / Relative weight: 1
ReflectionResolution: 1.62→87 Å / Num. obs: 284276 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 7.89 % / Biso Wilson estimate: 21.73 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 17.22
Reflection shellResolution: 1.62→1.66 Å / Redundancy: 5.09 % / Rmerge(I) obs: 0.4 / Mean I/σ(I) obs: 4.2 / % possible all: 99.8

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.62→68.06 Å / Cor.coef. Fo:Fc: 0.9644 / Cor.coef. Fo:Fc free: 0.9596 / SU R Cruickshank DPI: 0.066 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.068 / SU Rfree Blow DPI: 0.066 / SU Rfree Cruickshank DPI: 0.064
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY.
RfactorNum. reflection% reflectionSelection details
Rfree0.1789 5116 1.8 %RANDOM
Rwork0.1638 ---
obs0.1641 284274 99.74 %-
Displacement parametersBiso mean: 25.12 Å2
Baniso -1Baniso -2Baniso -3
1--0.1534 Å20 Å20 Å2
2--0.2328 Å20 Å2
3----0.0794 Å2
Refine analyzeLuzzati coordinate error obs: 0.155 Å
Refinement stepCycle: LAST / Resolution: 1.62→68.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11961 0 333 1590 13884
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0112792HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0517481HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4368SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes311HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1868HARMONIC5
X-RAY DIFFRACTIONt_it12792HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion4.3
X-RAY DIFFRACTIONt_other_torsion17.91
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1677SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact16099SEMIHARMONIC4
LS refinement shellResolution: 1.62→1.66 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.1959 374 1.8 %
Rwork0.1924 20403 -
all0.1925 20777 -
obs--99.74 %

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