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- PDB-1x70: HUMAN DIPEPTIDYL PEPTIDASE IV IN COMPLEX WITH A BETA AMINO ACID I... -

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Basic information

Entry
Database: PDB / ID: 1x70
TitleHUMAN DIPEPTIDYL PEPTIDASE IV IN COMPLEX WITH A BETA AMINO ACID INHIBITOR
ComponentsDipeptidyl peptidase IV
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 / intercellular canaliculus / psychomotor behavior / chemorepellent activity / 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 / intercellular canaliculus / psychomotor behavior / chemorepellent activity / dipeptidyl-peptidase activity / peptide hormone processing / locomotory exploration behavior / lamellipodium membrane / endocytic vesicle / behavioral fear response / endothelial cell migration / aminopeptidase activity / 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 / 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 / serine-type endopeptidase activity / signaling receptor binding / 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 / 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 ...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-715 / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsKim, D. / Wang, L. / Beconi, M. / Eiermann, G.J. / Fisher, M.H. / He, H. / Hickey, G.J. / Leiting, B. / Lyons, K.
CitationJournal: J.Med.Chem. / Year: 2005
Title: (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-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the ...Title: (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-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes
Authors: Kim, D. / Wang, L. / Beconi, M. / Eiermann, G.J. / Fisher, M.H. / He, H. / Hickey, G.J. / Kowalchick, J.E. / Leiting, B. / Lyons, K. / Marsilio, F. / McCann, M.E. / Patel, R.A. / Petrov, A. ...Authors: Kim, D. / Wang, L. / Beconi, M. / Eiermann, G.J. / Fisher, M.H. / He, H. / Hickey, G.J. / Kowalchick, J.E. / Leiting, B. / Lyons, K. / Marsilio, F. / McCann, M.E. / Patel, R.A. / Petrov, A. / Scapin, G. / Patel, S.B. / Roy, R.S. / Wu, J.K. / Wyvratt, M.J. / Zhang, B.B. / Zhu, L. / Thornberry, N.A. / Weber, A.E.
History
DepositionAug 12, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Jun 20, 2012Group: Non-polymer description
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_struct_conn_angle / 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_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _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_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_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 23, 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

Downloads & links

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Assembly

Deposited unit
A: Dipeptidyl peptidase IV
B: Dipeptidyl peptidase IV
hetero molecules


Theoretical massNumber of molelcules
Total (without water)174,93820
Polymers168,9532
Non-polymers5,98418
Water18,8801048
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12290 Å2
ΔGint64 kcal/mol
Surface area60020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.253, 125.680, 137.206
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 IV / DPP IV / T-cell activation antigen CD26 / TP103 / Adenosine deaminase complexing protein-2 / ADABP


Mass: 84476.648 Da / Num. of mol.: 2 / Fragment: extracellular domain / Mutation: S39T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Cell line (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P27487, dipeptidyl-peptidase IV

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Sugars , 3 types, 15 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-alpha-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
DGlcpNAca1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a2122h-1a_1-5_2*NCC/3=O]/1-2/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: 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.: 7
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)][a-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: 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.: 6
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, 1051 molecules

#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: 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
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1048 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.99 Å3/Da / Density % sol: 59.22 %
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: Jun 16, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. all: 119483 / Num. obs: 119408 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.3 % / Biso Wilson estimate: 29.4 Å2 / Rmerge(I) obs: 0.093 / Net I/σ(I): 9.9
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 7.7 % / Rmerge(I) obs: 0.4 / Mean I/σ(I) obs: 2 / Num. unique all: 11785 / % possible all: 100

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Processing

Software
NameClassification
HKL-2000data collection
SCALEPACKdata scaling
CNXrefinement
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1N1M

1n1m


Resolution: 2.1→30 Å / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: ENGH & HUBER
RfactorNum. reflection% reflectionSelection details
Rfree0.228 6018 5 %RANDOM
Rwork0.193 ---
all-119483 --
obs-119311 99.9 %-
Solvent computationSolvent model: MASK / Bsol: 40.1 Å2 / ksol: 0.364 e/Å3
Displacement parametersBiso mean: 28.5 Å2
Baniso -1Baniso -2Baniso -3
1-4.982 Å20 Å20 Å2
2---3.2 Å20 Å2
3----1.692 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.23 Å0.18 Å
Refinement stepCycle: LAST / Resolution: 2.1→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11930 0 393 1048 13371
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.44
X-RAY DIFFRACTIONc_dihedral_angle_d24.77
X-RAY DIFFRACTIONc_improper_angle_d0.835
X-RAY DIFFRACTIONc_mcbond_it0.981.5
X-RAY DIFFRACTIONc_mcangle_it1.542
X-RAY DIFFRACTIONc_scbond_it1.622
X-RAY DIFFRACTIONc_scangle_it2.422.5
LS refinement shellResolution: 2.1→2.18 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.311 601 5.1 %
Rwork0.258 11139 -
obs-11740 99.6 %
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1PROTEIN_REP.PARAM
X-RAY DIFFRACTION2WATER_REP.PARAM
X-RAY DIFFRACTION3ION.PARAM
X-RAY DIFFRACTION4CARBOHYDRATE.PARAM

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