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- PDB-3g0b: Crystal structure of dipeptidyl peptidase IV in complex with TAK-322 -

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Basic information

Entry
Database: PDB / ID: 3g0b
TitleCrystal structure of dipeptidyl peptidase IV in complex with TAK-322
ComponentsDipeptidyl peptidase 4Dipeptidyl peptidase-4
KeywordsHYDROLASE/HYDROLASE INHIBITOR / protease and 8-bladed beta-propeller domain / Aminopeptidase / Cell membrane / Glycoprotein / Hydrolase / Membrane / Protease / Secreted / 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-T22 / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsZhang, Z. / Wallace, M.B. / Feng, J. / Stafford, J.A. / Kaldor, S.W. / Shi, L. / Skene, R.J. / Aertgeerts, K. / Lee, B. / Jennings, A. ...Zhang, Z. / Wallace, M.B. / Feng, J. / Stafford, J.A. / Kaldor, S.W. / Shi, L. / Skene, R.J. / Aertgeerts, K. / Lee, B. / Jennings, A. / Xu, R. / Kassel, D. / Webb, D.R. / Gwaltney, S.L.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Design and Synthesis of Pyrimidinone and Pyrimidinedione Inhibitors of Dipeptidyl Peptidase IV.
Authors: Zhang, Z. / Wallace, M.B. / Feng, J. / Stafford, J.A. / Skene, R.J. / Shi, L. / Lee, B. / Aertgeerts, K. / Jennings, A. / Xu, R. / Kassel, D.B. / Kaldor, S.W. / Navre, M. / Webb, D.R. / Gwaltney, S.L.
History
DepositionJan 27, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 16, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Apr 6, 2016Group: Non-polymer description
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 / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_close_contact / 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 / _pdbx_unobs_or_zero_occ_atoms.auth_asym_id / _pdbx_unobs_or_zero_occ_atoms.auth_seq_id / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_2 / _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_conn.ptnr2_label_atom_id / _struct_ref_seq_dif.details
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
B: Dipeptidyl peptidase 4
C: Dipeptidyl peptidase 4
D: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)351,61733
Polymers343,1044
Non-polymers8,51329
Water10,034557
1
A: Dipeptidyl peptidase 4
B: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)176,54718
Polymers171,5522
Non-polymers4,99516
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4390 Å2
ΔGint-16.5 kcal/mol
Surface area57720 Å2
MethodPISA
2
C: Dipeptidyl peptidase 4
D: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,07015
Polymers171,5522
Non-polymers3,51813
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4450 Å2
ΔGint-16.3 kcal/mol
Surface area57330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.686, 122.398, 144.010
Angle α, β, γ (deg.)90.00, 114.72, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Dipeptidyl peptidase 4 / Dipeptidyl peptidase-4 / Dipeptidyl peptidase IV / DPP IV / T-cell activation antigen CD26 / TP103 / Adenosine deaminase ...Dipeptidyl peptidase IV / DPP IV / T-cell activation antigen CD26 / TP103 / Adenosine deaminase complexing protein 2 / ADABP / Dipeptidyl peptidase 4 membrane form / Dipeptidyl peptidase IV membrane form / Dipeptidyl peptidase 4 soluble form / Dipeptidyl peptidase IV soluble form


Mass: 85775.945 Da / Num. of mol.: 4 / Fragment: UNP residues 39-766
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADCP2, CD26, DPP4 / Plasmid: pFASTBAC / Cell line (production host): Sf9 / 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


Mass: 424.401 Da / Num. of mol.: 8
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-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 17
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-T22 / 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile / Alogliptin / Alogliptin


Mass: 339.392 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H21N5O2 / Comment: inhibitor*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 557 / 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: 2.84 Å3/Da / Density % sol: 56.68 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: 22% PEG MME 2000, 0.06M NP_Bicine_Na, 0.04M Bicine, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.25→35 Å / Num. obs: 182012

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Processing

Software
NameVersionClassification
ADSCQUANTUMdata collection
PHASERphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→35 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.932 / SU B: 13.97 / SU ML: 0.178 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.288 / ESU R Free: 0.215 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.24245 8857 5 %RANDOM
Rwork0.20675 ---
obs0.20855 168006 97.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.676 Å2
Baniso -1Baniso -2Baniso -3
1--1.98 Å20 Å20.23 Å2
2--2.55 Å20 Å2
3----0.38 Å2
Refinement stepCycle: LAST / Resolution: 2.25→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23873 0 562 557 24992
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.02225170
X-RAY DIFFRACTIONr_angle_refined_deg1.2841.95434266
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.33952909
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.63923.9561236
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.974153987
X-RAY DIFFRACTIONr_dihedral_angle_4_deg1815119
X-RAY DIFFRACTIONr_chiral_restr0.0890.23661
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219257
X-RAY DIFFRACTIONr_nbd_refined0.2010.211938
X-RAY DIFFRACTIONr_nbtor_refined0.3110.216953
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1290.21293
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2010.268
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1290.28
X-RAY DIFFRACTIONr_mcbond_it0.4351.514863
X-RAY DIFFRACTIONr_mcangle_it0.742223540
X-RAY DIFFRACTIONr_scbond_it1.089312148
X-RAY DIFFRACTIONr_scangle_it1.6784.510725
LS refinement shellResolution: 2.25→2.31 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 530 -
Rwork0.285 9868 -
obs--77.61 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.96550.1617-0.38070.71860.27291.4753-0.0686-0.5252-0.33630.27720.0395-0.32260.07120.4460.0291-0.12490.0524-0.06520.02920.0804-0.095956.136134.537628.6239
22.23490.2167-0.28661.04330.03271.2091-0.11640.2348-0.2934-0.16580.0957-0.0720.01550.08740.0207-0.24050.01130.0365-0.2436-0.0183-0.218238.411429.89913.4946
32.28310.5387-0.0350.79320.34750.9223-0.1017-0.3340.1375-0.03420.07350.3038-0.2366-0.33120.0283-0.14230.11540.0568-0.02780.0918-0.0957-13.590332.960326.8222
42.17930.29920.08610.8201-0.13991.1678-0.11340.0068-0.6614-0.06830.09420.03440.2186-0.0790.0192-0.22230.01560.0717-0.24980.06210.01235.48713.014312.6316
52.93281.00860.1831.8952-0.5381.24760.2044-0.5404-0.66950.2406-0.4405-0.93120.15360.77360.23610.0178-0.0076-0.17170.32090.34390.231395.8698-38.909252.5781
62.96040.89430.04811.7087-0.28441.33720.1655-0.20270.51190.1252-0.1962-0.2521-0.32720.29980.0307-0.0805-0.07760.002-0.21360.0132-0.072481.7377-14.566239.5712
73.0185-0.09890.87480.5145-0.38821.32040.0982-0.68590.11530.1935-0.00950.2366-0.1256-0.6184-0.0887-0.09370.00760.07490.14150.0256-0.153327.1107-32.079141.0177
82.65720.20210.39950.9192-0.11271.31910.05760.42880.3522-0.1535-0.0440.0459-0.1756-0.1325-0.0136-0.15980.09120.0398-0.18220.0921-0.22750.0148-24.926121.1233
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A61 - 495
2X-RAY DIFFRACTION2A497 - 766
3X-RAY DIFFRACTION3B61 - 495
4X-RAY DIFFRACTION4B497 - 766
5X-RAY DIFFRACTION5C61 - 495
6X-RAY DIFFRACTION6C497 - 766
7X-RAY DIFFRACTION7D61 - 495
8X-RAY DIFFRACTION8D497 - 766

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