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- PDB-2iiv: Human dipeptidyl peptidase 4 in complex with a diazepan-2-one inh... -

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Basic information

Entry
Database: PDB / ID: 2iiv
TitleHuman dipeptidyl peptidase 4 in complex with a diazepan-2-one inhibitor
ComponentsDipeptidyl peptidase 4 soluble form
KeywordsHYDROLASE / ALPHA/BETA / BETA-PROPELLER / DIMER
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-565 / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.15 Å
AuthorsScapin, G. / Weber, A.E. / Biftu, T.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: (3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
Authors: Biftu, T. / Feng, D. / Qian, X. / Liang, G.B. / Kieczykowski, G. / Eiermann, G. / He, H. / Leiting, B. / Lyons, K. / Petrov, A. / Sinha-Roy, R. / Zhang, B. / Scapin, G. / Patel, S. / Gao, Y. ...Authors: Biftu, T. / Feng, D. / Qian, X. / Liang, G.B. / Kieczykowski, G. / Eiermann, G. / He, H. / Leiting, B. / Lyons, K. / Petrov, A. / Sinha-Roy, R. / Zhang, B. / Scapin, G. / Patel, S. / Gao, Y.D. / Singh, S. / Wu, J. / Zhang, X. / Thornberry, N.A. / Weber, A.E.
History
DepositionSep 28, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 28, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / 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 / pdbx_validate_chiral / 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 / _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_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.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 20, 2021Group: Database references / Structure summary / Category: chem_comp / database_2 / struct_ref_seq_dif
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 2.2Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)174,56618
Polymers168,9532
Non-polymers5,61216
Water16,574920
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11760 Å2
ΔGint59 kcal/mol
Surface area59650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.192, 125.777, 136.902
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 soluble form / E.C.3.4.14.5 / Dipeptidyl peptidase IV soluble form


Mass: 84476.648 Da / Num. of mol.: 2 / Fragment: EXTRACELLULAR DOMAIN (residues 39-766) / Mutation: Ser39Thr
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf21 / 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)][a-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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5
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-565 / (3R)-4-[(3R)-3-AMINO-4-(2,4,5-TRIFLUOROPHENYL)BUTANOYL]-3-METHYL-1,4-DIAZEPAN-2-ONE


Mass: 343.344 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H20F3N3O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 920 / 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: 3.01 Å3/Da / Density % sol: 59.14 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: PEG 4000, SODIUM ACETATE, TRIS, pH 8.00, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 32-ID / Wavelength: 1 / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jul 16, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. all: 111431 / Num. obs: 107977 / % possible obs: 96.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.6 % / Biso Wilson estimate: 29.4 Å2 / Rmerge(I) obs: 0.109 / Net I/σ(I): 5.4
Reflection shellResolution: 2.15→2.23 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.418 / Mean I/σ(I) obs: 1.2 / Num. unique all: 8273 / % possible all: 86.6

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT2data extraction
MAR345345DTBdata collection
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing
CNXrefinement
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1X70

1x70


Resolution: 2.15→30 Å / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.229 5435 4.9 %RANDOM
Rwork0.194 ---
obs0.197 107775 96.9 %-
all-111220 --
Solvent computationSolvent model: MASK / Bsol: 25.8 Å2 / ksol: 0.329 e/Å3
Displacement parametersBiso mean: 28.3 Å2
Baniso -1Baniso -2Baniso -3
1-6.069 Å20 Å20 Å2
2---5.08 Å20 Å2
3----0.989 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.22 Å0.2 Å
Refinement stepCycle: LAST / Resolution: 2.15→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11930 0 370 920 13220
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.47
X-RAY DIFFRACTIONc_dihedral_angle_d24.9
X-RAY DIFFRACTIONc_improper_angle_d0.867
X-RAY DIFFRACTIONc_mcbond_it0.921.5
X-RAY DIFFRACTIONc_mcangle_it1.492
X-RAY DIFFRACTIONc_scbond_it1.452
X-RAY DIFFRACTIONc_scangle_it2.22.5
LS refinement shellResolution: 2.15→2.23 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.273 356 4.3 %
Rwork0.239 7115 -
obs-9546 86.7 %

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