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- PDB-4lko: Crystal structure of human DPP-IV in complex with BMS-744891 -

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Basic information

Entry
Database: PDB / ID: 4lko
TitleCrystal structure of human DPP-IV in complex with BMS-744891
ComponentsDipeptidyl peptidase 4Dipeptidyl peptidase-4
KeywordsHYDROLASE / exopeptidase / beta barrel / alpha/beta hydrolase fold
Function / homology
Function and homology information


glucagon processing / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / negative regulation of neutrophil chemotaxis / regulation of cell-cell adhesion mediated by integrin / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / psychomotor behavior / intercellular canaliculus / chemorepellent activity / dipeptidyl-peptidase activity ...glucagon processing / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / negative regulation of neutrophil chemotaxis / regulation of cell-cell adhesion mediated by integrin / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / psychomotor behavior / 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 / serine-type peptidase activity / T cell activation / 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-1WH / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsKlei, H.E.
Citation
Journal: J.Med.Chem. / Year: 2013
Title: Optimization of Activity, Selectivity, and Liability Profiles in 5-Oxopyrrolopyridine DPP4 Inhibitors Leading to Clinical Candidate (Sa)-2-(3-(Aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5- ...Title: Optimization of Activity, Selectivity, and Liability Profiles in 5-Oxopyrrolopyridine DPP4 Inhibitors Leading to Clinical Candidate (Sa)-2-(3-(Aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778).
Authors: Devasthale, P. / Wang, Y. / Wang, W. / Fevig, J. / Feng, J. / Wang, A. / Harrity, T. / Egan, D. / Morgan, N. / Cap, M. / Fura, A. / Klei, H.E. / Kish, K. / Weigelt, C. / Sun, L. / Levesque, ...Authors: Devasthale, P. / Wang, Y. / Wang, W. / Fevig, J. / Feng, J. / Wang, A. / Harrity, T. / Egan, D. / Morgan, N. / Cap, M. / Fura, A. / Klei, H.E. / Kish, K. / Weigelt, C. / Sun, L. / Levesque, P. / Moulin, F. / Li, Y.X. / Zahler, R. / Kirby, M.S. / Hamann, L.G.
#1: Journal: Structure / Year: 2003
Title: Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV.
Authors: Thoma, R. / Loffler, B. / Stihle, M. / Huber, W. / Ruf, A. / Hennig, M.
History
DepositionJul 8, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2013Group: Database references
Revision 1.2Apr 3, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,6864
Polymers168,9252
Non-polymers7612
Water1,76598
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4350 Å2
ΔGint-18 kcal/mol
Surface area58900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.900, 68.300, 421.500
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Dipeptidyl peptidase 4 / 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 / Dipeptidyl peptidase 4 membrane form / Dipeptidyl peptidase IV membrane form / Dipeptidyl peptidase 4 soluble form / Dipeptidyl peptidase IV soluble form


Mass: 84462.617 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Plasmid: pPICZ-A / Production host: Komagataella pastoris (fungus) / Strain (production host): KM71H / References: UniProt: P27487, dipeptidyl-peptidase IV
#2: Chemical ChemComp-1WH / 3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-(2-methoxyethyl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one


Mass: 380.268 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H19Cl2N3O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 2.81 Å3/Da / Density % sol: 56.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 100 mM Bis-Tris-Propane, pH 7.8?, 200 mM MGCL2, 15.9%(W/V) PEG 3350, 15%(V/V) Glycerol, vapor diffusion, hanging drop, temperature 293K
PH range: 7.8?

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.1 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 30, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.42→50 Å / Num. obs: 70295 / % possible obs: 97.3 % / Observed criterion σ(I): 0 / Redundancy: 5.9 % / Biso Wilson estimate: 46 Å2 / Rmerge(I) obs: 0.114 / Net I/σ(I): 16.5
Reflection shellResolution: 2.42→2.51 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.368 / Mean I/σ(I) obs: 3 / % possible all: 83.9

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
DENZOdata reduction
SCALEPACKdata scaling
CNXphasing
CNX2002refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: X05-052

Resolution: 2.43→47.43 Å / Rfactor Rfree error: 0.004 / Occupancy max: 1 / Occupancy min: 1 / Data cutoff high absF: 2423470 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.263 4996 7.1 %RANDOM
Rwork0.226 ---
obs-70190 96.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 22.0821 Å2 / ksol: 0.3068 e/Å3
Displacement parametersBiso max: 90.29 Å2 / Biso mean: 51.988 Å2 / Biso min: 24.78 Å2
Baniso -1Baniso -2Baniso -3
1-11.39 Å20 Å20 Å2
2--6.17 Å20 Å2
3----17.57 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.4 Å0.35 Å
Luzzati d res low-5 Å
Luzzati sigma a0.45 Å0.38 Å
Refinement stepCycle: LAST / Resolution: 2.43→47.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11926 0 50 98 12074
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d24.8
X-RAY DIFFRACTIONc_improper_angle_d0.83
X-RAY DIFFRACTIONc_mcbond_it1.351.5
X-RAY DIFFRACTIONc_mcangle_it2.232
X-RAY DIFFRACTIONc_scbond_it2.342
X-RAY DIFFRACTIONc_scangle_it3.362.5
LS refinement shellResolution: 2.43→2.53 Å / Rfactor Rfree error: 0.019 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.384 425 7.2 %
Rwork0.34 5505 -
all-5930 -
obs--64.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4INH.parINH.top

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