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- PDB-4ffw: Crystal Structure of Dipeptidyl Peptidase IV (DPP4, DPP-IV, CD26)... -

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Basic information

Entry
Database: PDB / ID: 4ffw
TitleCrystal Structure of Dipeptidyl Peptidase IV (DPP4, DPP-IV, CD26) in Complex with Fab + sitagliptin
Components
  • Dipeptidyl peptidase 4
  • Fab heavy chain
  • Fab light chain
KeywordsHYDROLASE/Immune System / INHIBITOR / hydrolase / HYDROLASE-Immune System / INHIBITOR complex
Function / homology
Function and homology information


B-1a B cell differentiation / regulation of T cell mediated immunity / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / positive regulation of natural killer cell mediated immunity / negative regulation of neutrophil chemotaxis / regulation of cell-cell adhesion mediated by integrin / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / intercellular canaliculus ...B-1a B cell differentiation / regulation of T cell mediated immunity / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / positive regulation of natural killer cell mediated immunity / negative regulation of neutrophil chemotaxis / regulation of cell-cell adhesion mediated by integrin / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / intercellular canaliculus / psychomotor behavior / chemorepellent activity / dipeptidyl-peptidase activity / locomotory exploration behavior / lamellipodium membrane / endocytic vesicle / behavioral fear response / endothelial cell migration / aminopeptidase activity / collagen binding / T cell costimulation / serine-type peptidase activity / T cell activation / peptide binding / protein catabolic process / lamellipodium / virus receptor activity / protease binding / response to hypoxia / cell adhesion / membrane raft / apical plasma membrane / serine-type endopeptidase activity / signaling receptor binding / positive regulation of cell population proliferation / cell surface / protein homodimerization activity / proteolysis / extracellular region / identical protein binding / plasma membrane
Similarity search - Function
Dipeptidyl peptidase 4, low complexity region / Dipeptidyl peptidase IV (DPP IV) low complexity region / 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 ...Dipeptidyl peptidase 4, low complexity region / Dipeptidyl peptidase IV (DPP IV) low complexity region / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-715 / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsWang, Z. / Sudom, A. / Walker, N.P. / Min, X.
CitationJournal: To be published
Title: An Inhibitory Antibody Against DPP IV Improves Glucose Tolerance in vivo - Validation of Large Molecule Approach for DPP IV Inhibition
Authors: Tang, J. / Majeti, J. / Sudom, A. / Xiong, Y. / Lu, M. / Liu, Q. / Higbee, J. / Zhang, Y. / Wang, Y. / Wang, W. / Cao, P. / Xia, Z. / Johnstone, S. / Yang, X. / Yu, T. / Sharkov, N. / ...Authors: Tang, J. / Majeti, J. / Sudom, A. / Xiong, Y. / Lu, M. / Liu, Q. / Higbee, J. / Zhang, Y. / Wang, Y. / Wang, W. / Cao, P. / Xia, Z. / Johnstone, S. / Yang, X. / Yu, T. / Sharkov, N. / Walker, N. / Tu, H. / Shen, W. / Wang, Z.
History
DepositionJun 1, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 12, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 6, 2018Group: Data collection / Category: diffrn_radiation_wavelength / diffrn_source / Item: _diffrn_source.pdbx_wavelength_list
Revision 1.2May 19, 2021Group: Derived calculations / Source and taxonomy / Structure summary
Category: chem_comp / entity ...chem_comp / entity / entity_src_gen / pdbx_entity_nonpoly / struct_site
Item: _chem_comp.name / _entity.pdbx_description ..._chem_comp.name / _entity.pdbx_description / _entity_src_gen.host_org_common_name / _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_strain / _pdbx_entity_nonpoly.name / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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: Fab light chain
D: Fab heavy chain
H: Fab heavy chain
L: Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)261,8948
Polymers261,0806
Non-polymers8152
Water70339
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)97.770, 200.860, 97.930
Angle α, β, γ (deg.)90.00, 93.64, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Dipeptidyl peptidase 4 / Bile canaliculus domain-specific membrane glycoprotein / Dipeptidyl peptidase IV / DPP IV / GP110 ...Bile canaliculus domain-specific membrane glycoprotein / Dipeptidyl peptidase IV / DPP IV / GP110 glycoprotein / T-cell activation antigen CD26 / Dipeptidyl peptidase 4 membrane form / Dipeptidyl peptidase IV membrane form / Dipeptidyl peptidase 4 soluble form / Dipeptidyl peptidase IV soluble form / Dipeptidyl peptidase 4 60 kDa soluble form / Dipeptidyl peptidase IV 60 kDa soluble form


Mass: 84337.578 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Dpp4, Cd26 / Cell line (production host): HEK293 6E / Production host: Homo sapiens (human) / References: UniProt: P14740, dipeptidyl-peptidase IV
#2: Antibody Fab light chain


Mass: 22895.209 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#3: Antibody Fab heavy chain


Mass: 23307.127 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#4: Chemical ChemComp-715 / (2R)-4-OXO-4-[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]-1-(2,4,5-TRIFLUOROPHENYL)BUTAN-2-A MINE / Sitagliptin


Mass: 407.314 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H15F6N5O / Comment: medication*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 3.68 Å3/Da / Density % sol: 66.54 %
Crystal growTemperature: 289 K / Method: vapor diffusion / pH: 7.9
Details: 2.2-2.7 M ammonium sulfate, 0.1 M Tris 7.5-7.9, vapor diffusion, temperature 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 15, 2010 / Details: 3X3 CCD ARRAY
RadiationMonochromator: DOUBLE-CRYSTAL, SI (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→100.43 Å / Num. all: 82634 / Num. obs: 82634 / % possible obs: 99.2 % / Redundancy: 3.7 % / Rsym value: 0.08 / Net I/σ(I): 10.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRsym valueDiffraction-ID% possible all
2.9-3.063.80.4221.70.422199.2
3.06-3.243.80.2492.90.249199.2
3.24-3.473.80.1534.60.153199.3
3.47-3.743.80.1016.40.101199.4
3.74-4.13.70.0797.90.079199.5
4.1-4.593.70.0629.60.062199.7
4.59-5.293.70.057100.057199.6
5.29-6.483.60.0619.60.061199.1
6.48-9.173.50.05111.10.051196.5
9.17-71.3533.80.0511.40.05199.5

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.15data scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→29.99 Å / Cor.coef. Fo:Fc: 0.88 / Cor.coef. Fo:Fc free: 0.86 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 22.094 / SU ML: 0.416 / SU R Cruickshank DPI: 1.4751 / Cross valid method: THROUGHOUT / ESU R: 1.566 / ESU R Free: 0.444 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31094 4123 5 %RANDOM
Rwork0.28654 ---
obs0.28777 78420 99.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 93.533 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å2-0 Å2-0.01 Å2
2--0.1 Å20 Å2
3----0.04 Å2
Refinement stepCycle: LAST / Resolution: 2.9→29.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms18171 0 56 39 18266
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.01918746
X-RAY DIFFRACTIONr_bond_other_d0.0010.0217019
X-RAY DIFFRACTIONr_angle_refined_deg0.7971.93825535
X-RAY DIFFRACTIONr_angle_other_deg0.6483.00239236
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.55652272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.29524.196846
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.698153017
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.0521575
X-RAY DIFFRACTIONr_chiral_restr0.0480.22769
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.02121226
X-RAY DIFFRACTIONr_gen_planes_other0.0010.024461
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_it0.7051.511528
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.35218720
X-RAY DIFFRACTIONr_scbond_it1.76237423
X-RAY DIFFRACTIONr_scangle_it3.0174.57097
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.424 300 -
Rwork0.386 5784 -
obs--99.22 %

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