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- PDB-5kby: Crystal structure of dipeptidyl peptidase IV in complex with SYR-472 -

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Basic information

Entry
Database: PDB / ID: 5kby
TitleCrystal structure of dipeptidyl peptidase IV in complex with SYR-472
ComponentsDipeptidyl peptidase 4
KeywordsHYDROLASE/HYDROLASE INHIBITOR / peptidase / glp-1 / metabolic disease / co-complex / HYDROLASE-HYDROLASE INHIBITOR complex
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 / membrane fusion / receptor-mediated endocytosis of virus by host cell / 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-6RL / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.24 Å
AuthorsSkene, R.J. / Jennings, A.J.
CitationJournal: Plos One / Year: 2016
Title: Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism.
Authors: Grimshaw, C.E. / Jennings, A. / Kamran, R. / Ueno, H. / Nishigaki, N. / Kosaka, T. / Tani, A. / Sano, H. / Kinugawa, Y. / Koumura, E. / Shi, L. / Takeuchi, K.
History
DepositionJun 3, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 13, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2016Group: Non-polymer description
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / 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_oper_list / pdbx_validate_close_contact / 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 / _atom_site_anisotrop.id / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_oper_list.symmetry_operation / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_seq_id_1 / _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 2.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)350,39829
Polymers343,1044
Non-polymers7,29425
Water28,7701597
1
A: Dipeptidyl peptidase 4
B: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,73416
Polymers171,5522
Non-polymers4,18214
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8540 Å2
ΔGint38 kcal/mol
Surface area59340 Å2
MethodPISA
2
C: Dipeptidyl peptidase 4
D: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)174,66413
Polymers171,5522
Non-polymers3,11211
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7450 Å2
ΔGint21 kcal/mol
Surface area58290 Å2
MethodPISA
3
A: Dipeptidyl peptidase 4
B: Dipeptidyl peptidase 4
hetero molecules

C: Dipeptidyl peptidase 4
D: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)350,39829
Polymers343,1044
Non-polymers7,29425
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_656-x+1,y+1/2,-z+11
Buried area16620 Å2
ΔGint57 kcal/mol
Surface area116990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.573, 122.165, 143.704
Angle α, β, γ (deg.)90.000, 114.570, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 85775.945 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Production host: unidentified baculovirus / 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.: 6
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-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.: 15
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-6RL / 2-[[6-[(3~{R})-3-azanylpiperidin-1-yl]-3-methyl-2,4-bis(oxidanylidene)pyrimidin-1-yl]methyl]-4-fluoranyl-benzenecarboni trile / SYR-472


Mass: 357.382 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H20FN5O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1597 / 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: 2.85 Å3/Da / Density % sol: 56.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 22.2% PEG MME 2000, 0.1M Bicine pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 11, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. obs: 178650 / % possible obs: 98.9 % / Redundancy: 4 % / Rmerge(I) obs: 0.083 / Χ2: 1.009 / Net I/av σ(I): 14.475 / Net I/σ(I): 9.5 / Num. measured all: 712558
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.25-2.32.90.541188.8
2.3-2.363.30.523195.8
2.36-2.423.70.478199.1
2.42-2.540.438199.9
2.5-2.584.10.3881100
2.58-2.674.20.3061100
2.67-2.774.20.2471100
2.77-2.94.20.1841100
2.9-3.054.20.141100
3.05-3.244.20.1051100
3.24-3.54.20.0861100
3.5-3.854.10.0721100
3.85-4.44.10.0541100
4.4-5.554.10.0391100
5.55-504.20.031199.9

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Processing

Software
NameVersionClassification
REFMAC5.7.0025refinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3G0B

3g0b


Resolution: 2.24→34.57 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.943 / SU B: 10.877 / SU ML: 0.143 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.251 / ESU R Free: 0.193 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.215 8950 5 %RANDOM
Rwork0.1743 ---
obs0.1764 169608 97.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 144.65 Å2 / Biso mean: 50.867 Å2 / Biso min: 19.67 Å2
Baniso -1Baniso -2Baniso -3
1--0.16 Å20 Å20 Å2
2--0.25 Å20 Å2
3----0.09 Å2
Refinement stepCycle: final / Resolution: 2.24→34.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23764 0 482 1597 25843
Biso mean--65.64 46.22 -
Num. residues----2900
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01925013
X-RAY DIFFRACTIONr_bond_other_d0.0020.0222439
X-RAY DIFFRACTIONr_angle_refined_deg1.2461.95234056
X-RAY DIFFRACTIONr_angle_other_deg0.7423.00251455
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.41152890
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.00623.9011228
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.866153974
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.48915120
X-RAY DIFFRACTIONr_chiral_restr0.0760.23629
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0228170
X-RAY DIFFRACTIONr_gen_planes_other0.0010.026128
LS refinement shellResolution: 2.243→2.301 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.306 520 -
Rwork0.278 9615 -
all-10135 -
obs--75.51 %
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)
10.71210.1281-0.03540.15160.02920.2967-0.0229-0.0766-0.14440.0125-0.0025-0.0494-0.04850.06880.02540.05150.0151-0.01470.05750.020.093449.463831.999818.7043
20.97310.0704-0.18320.05570.01970.3068-0.044-0.0695-0.1415-0.01430.02880.003-0.0595-0.04140.01520.04630.02110.01290.05420.04240.0895-6.414225.197920.1457
31.16670.382-0.11430.47-0.33520.29140.1107-0.2665-0.0825-0.0027-0.2114-0.1301-0.02580.14320.10070.1217-0.0406-0.01730.11590.07170.068690.5409-29.103847.1054
41.35720.06390.25420.0394-0.03250.24770.0486-0.09820.114-0.0026-0.0097-0.0088-0.0152-0.1498-0.03890.08550.02620.01820.12840.05940.052535.853-28.526133.4098
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A40 - 766
2X-RAY DIFFRACTION2B36 - 766
3X-RAY DIFFRACTION3C40 - 766
4X-RAY DIFFRACTION4D40 - 766

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