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- PDB-2ajl: X-ray Structure of Novel Biaryl-Based Dipeptidyl peptidase IV inh... -

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Basic information

Entry
Database: PDB / ID: 2ajl
TitleX-ray Structure of Novel Biaryl-Based Dipeptidyl peptidase IV inhibitor
ComponentsDipeptidyl peptidase 4Dipeptidyl peptidase-4
KeywordsHYDROLASE / Aminopeptidase / protease / serine protease
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-JNH / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsQiao, L. / Baumann, C.A. / Crysler, C.S. / Ninan, N.S. / Abad, M.C. / Spurlino, J.C. / DesJarlais, R.L. / Kervinen, J. / Neeper, M.P. / Bayoumy, S.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Discovery, SAR, and X-ray structure of novel biaryl-based dipeptidyl peptidase IV inhibitors
Authors: Qiao, L. / Baumann, C.A. / Crysler, C.S. / Ninan, N.S. / Abad, M.C. / Spurlino, J.C. / Desjarlais, R.L. / Kervinen, J. / Neeper, M.P. / Bayoumy, S.S. / Williams, R. / Deckman, I.C. / ...Authors: Qiao, L. / Baumann, C.A. / Crysler, C.S. / Ninan, N.S. / Abad, M.C. / Spurlino, J.C. / Desjarlais, R.L. / Kervinen, J. / Neeper, M.P. / Bayoumy, S.S. / Williams, R. / Deckman, I.C. / Dasgupta, M. / Reed, R.L. / Huebert, N.D. / Tomczuk, B.E. / Moriarty, K.J.
History
DepositionAug 2, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 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 1.3Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Structure summary
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_unobs_or_zero_occ_atoms / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Aug 23, 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
I: Dipeptidyl peptidase 4
J: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)172,66918
Polymers168,9252
Non-polymers3,74416
Water7,260403
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8980 Å2
ΔGint30 kcal/mol
Surface area58870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.279, 126.877, 110.828
Angle α, β, γ (deg.)90.00, 99.41, 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


Mass: 84462.617 Da / Num. of mol.: 2
Fragment: Dipeptidyl peptidase 4 soluble form, residues 39-766
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Plasmid: pFastBac / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P27487, dipeptidyl-peptidase IV
#2: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 14 / Source method: obtained synthetically / 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
#3: Chemical ChemComp-JNH / 1-[2-(S)-AMINO-3-BIPHENYL-4-YL-PROPIONYL]-PYRROLIDINE-2-(S)-CARBONITRILE


Mass: 323.432 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H25N3O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 403 / 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: 2.7 Å3/Da / Density % sol: 54 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: PEG 4000, Tris, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER / Wavelength: 1.5418 Å
DetectorType: BRUKER SMART 6000 / Detector: CCD / Date: Nov 17, 2003 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→64.1 Å / Num. obs: 55940 / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 2.7 % / Biso Wilson estimate: 29 Å2 / Rmerge(I) obs: 0.374 / Rsym value: 0.123 / Net I/σ(I): 5.88
Reflection shellResolution: 2.5→2.63 Å / Redundancy: 2.7 % / Mean I/σ(I) obs: 1.6 / Rsym value: 0.358 / % possible all: 88

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Processing

Software
NameClassification
PROTEUM PLUSdata collection
PROTEUM PLUSdata reduction
CNSrefinement
PROTEUM PLUSdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1N1M

1n1m


Resolution: 2.5→64.1 Å / Isotropic thermal model: anisotropic / σ(F): 0 / σ(I): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.303 5678 -random
Rwork0.226 ---
all0.226 55940 --
obs-55940 90.8 %-
Refinement stepCycle: LAST / Resolution: 2.5→64.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11911 0 244 403 12558
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.012
X-RAY DIFFRACTIONc_angle_deg1.8
X-RAY DIFFRACTIONc_improper_angle_d0.82

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