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- PDB-3sx4: Crystal structure of human dpp-iv in complex with sa-(+)-3-(amino... -

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Basic information

Entry
Database: PDB / ID: 3sx4
TitleCrystal structure of human dpp-iv in complex with sa-(+)-3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-(2-methoxyphenyl)- 2-methyl-5h-pyrrolo[3,4-b]pyridin-7(6h)-one
ComponentsDipeptidyl peptidase 4Dipeptidyl peptidase-4
KeywordsHYDROLASE/HYDROLASE inhibitor / EXOPEPTIDASE / ALPHA/BETA HYDROLASE FOLD / BETA BARREL / BETA PROPELLER / DPP4 / DIMER / PROTEIN:INHIBITOR COMPLEX / AMINOPEPTIDASE / GLYCOPROTEIN / 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-KXA / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsKlei, H.E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: 7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site.
Authors: Wang, W. / Devasthale, P. / Wang, A. / Harrity, T. / Egan, D. / Morgan, N. / Cap, M. / Fura, A. / Klei, H.E. / Kish, K. / Weigelt, C. / Sun, L. / Levesque, P. / Li, Y.X. / Zahler, R. / Kirby, M.S. / Hamann, L.G.
History
DepositionJul 14, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 26, 2011Provider: repository / Type: Initial release
Revision 1.1May 23, 2012Group: Database references
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 / 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_alt_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.occupancy / _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.label_asym_id / _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_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Sep 13, 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

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Assembly

Deposited unit
A: Dipeptidyl peptidase 4
B: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)179,04017
Polymers174,9022
Non-polymers4,13915
Water41423
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4350 Å2
ΔGint-16 kcal/mol
Surface area57040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.905, 67.854, 422.095
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 87450.844 Da / Num. of mol.: 2 / Fragment: unp residues 39-766
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Plasmid: pPICZalpha / Production host: Pichia pastoris (fungus) / 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.: 2
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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 11
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-KXA / 3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-(2-methoxyphenyl)-2-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one


Mass: 428.311 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H19Cl2N3O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 54.41 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: CRYSTALS GROWN IN 2 UL EQUIVOLUME MIXTURE OF PROTEIN SOLUTION (0.1 M NACL, 20 MM TRIS-HCL BUFFER PH 7.8, 9.8 MG/ML PROTEIN) AND CRYSTALLIZATION SOLUTION (17% W/V PEG 3350, 15% W/V GLYCEROL, ...Details: CRYSTALS GROWN IN 2 UL EQUIVOLUME MIXTURE OF PROTEIN SOLUTION (0.1 M NACL, 20 MM TRIS-HCL BUFFER PH 7.8, 9.8 MG/ML PROTEIN) AND CRYSTALLIZATION SOLUTION (17% W/V PEG 3350, 15% W/V GLYCEROL, 200 MM MGCL2, 100 MM TRIS-HCL BUFFER PH 8.5). SUFFICIENT 100 MM LIGAND STOCK SOLUTION (NEAT DMSO) ADDED TO ACHIEVE 1 MM LIGAND CONCENTRATION. SOAKED OVERNIGHT. HARVESTED DIRECTLY AND CRYO-STORED IN LN2. 2. For crystal 2:

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1
DetectorType: ADSC Q315 / Detector: CCD / Date: Jun 8, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 57759 / % possible obs: 96.5 % / Observed criterion σ(I): 0 / Redundancy: 7.7 % / Biso Wilson estimate: 51.47 Å2 / Rmerge(I) obs: 0.097 / Net I/σ(I): 19.4
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.539 / Mean I/σ(I) obs: 1.8 / % possible all: 74.5

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Processing

Software
NameVersionClassificationNB
PHENIXdev_780refinement
PDB_EXTRACT3.1data extraction
CBASSdata collection
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NOX.PDB

3nox


Resolution: 2.6→48.096 Å / Occupancy max: 1 / Occupancy min: 0.5 / SU ML: 0.82 / σ(F): 1.44 / Phase error: 29.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.275 2329 4.04 %
Rwork0.2033 --
obs0.2061 57656 96.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 30.117 Å2 / ksol: 0.312 e/Å3
Displacement parametersBiso max: 115.24 Å2 / Biso mean: 55.7224 Å2 / Biso min: 21.76 Å2
Baniso -1Baniso -2Baniso -3
1-6.5163 Å20 Å2-0 Å2
2--7.5139 Å2-0 Å2
3----14.0302 Å2
Refinement stepCycle: LAST / Resolution: 2.6→48.096 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11751 0 268 23 12042
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00812464
X-RAY DIFFRACTIONf_angle_d1.18916993
X-RAY DIFFRACTIONf_chiral_restr0.0761813
X-RAY DIFFRACTIONf_plane_restr0.0042129
X-RAY DIFFRACTIONf_dihedral_angle_d17.2974419
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 17

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5968-2.64980.3892820.32332229231167
2.6498-2.70740.41991040.32162745284981
2.7074-2.77040.43331270.32522998312591
2.7704-2.83970.36981460.30493198334496
2.8397-2.91650.37441400.283132973437100
2.9165-3.00230.29091530.261433623515100
3.0023-3.09920.35941420.254433343476100
3.0992-3.20990.30861280.241633493477100
3.2099-3.33840.30181520.237633273479100
3.3384-3.49030.31691480.232533813529100
3.4903-3.67420.29311450.215533703515100
3.6742-3.90430.27321410.184533613502100
3.9043-4.20560.21231190.163934093528100
4.2056-4.62860.19581330.136834203553100
4.6286-5.29760.20211570.144434313588100
5.2976-6.67160.24831610.18134763637100
6.6716-48.10450.28651510.19573640379199

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