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- PDB-3f8s: Crystal structure of dipeptidyl peptidase IV in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 3f8s
TitleCrystal structure of dipeptidyl peptidase IV in complex with inhibitor
ComponentsDipeptidyl peptidase 4
KeywordsHYDROLASE / Dipeptidyl peptidase 4 / complex / Aminopeptidase / Glycoprotein / Membrane / Protease / Secreted / Serine protease / Signal-anchor / Transmembrane
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 / 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) / 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-PF2 / Dipeptidyl peptidase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.43 Å
AuthorsAmmirati, M.J. / Liu, S. / Piotrowski, D.W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: a potent, selective, orally active dipeptidyl peptidase IV inhibitor.
Authors: Ammirati, M.J. / Andrews, K.M. / Boyer, D.D. / Brodeur, A.M. / Danley, D.E. / Doran, S.D. / Hulin, B. / Liu, S. / McPherson, R.K. / Orena, S.J. / Parker, J.C. / Polivkova, J. / Qiu, X. / ...Authors: Ammirati, M.J. / Andrews, K.M. / Boyer, D.D. / Brodeur, A.M. / Danley, D.E. / Doran, S.D. / Hulin, B. / Liu, S. / McPherson, R.K. / Orena, S.J. / Parker, J.C. / Polivkova, J. / Qiu, X. / Soglia, C.B. / Treadway, J.L. / VanVolkenburg, M.A. / Wilder, D.C. / Piotrowski, D.W.
History
DepositionNov 13, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 23, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
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 / pdbx_validate_close_contact / 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_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_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_leaving_atom_flag / _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 / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Sep 6, 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 / struct_ncs_dom_lim
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 2.2Oct 16, 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 4
B: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)176,39211
Polymers173,2982
Non-polymers3,0949
Water00
1
A: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,0855
Polymers86,6491
Non-polymers1,4364
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dipeptidyl peptidase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,3076
Polymers86,6491
Non-polymers1,6585
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4350 Å2
ΔGint-15 kcal/mol
Surface area58730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.429, 67.141, 421.529
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: PRO / End label comp-ID: PRO / Refine code: 1 / Auth seq-ID: 39 - 766 / Label seq-ID: 9 - 736

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein 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: 86648.922 Da / Num. of mol.: 2 / Fragment: UNP residues 31-766
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP4, ADCP2, CD26 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / 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.: 4
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.: 3
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-PF2 / 2-(4-{(3S,5S)-5-[(3,3-difluoropyrrolidin-1-yl)carbonyl]pyrrolidin-3-yl}piperazin-1-yl)pyrimidine


Mass: 366.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H24F2N6O / Comment: inhibitor*YM
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.67 Å3/Da / Density % sol: 53.96 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Dec 10, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 34242 / % possible obs: 75 % / Observed criterion σ(I): 2 / Redundancy: 3.9 % / Rmerge(I) obs: 0.109 / Net I/σ(I): 14
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.325 / Mean I/σ(I) obs: 2 / Num. unique all: 1121 / % possible all: 32

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Processing

Software
NameVersionClassification
HKL-2000data collection
REFMAC5.2.0003refinement
HKL-2000data reduction
HKL-2000data scaling
REFMAC5.2.0003phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 2QJR

2qjr


Resolution: 2.43→50 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.885 / SU B: 26.392 / SU ML: 0.277 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: isotropic + TLS / Cross valid method: THROUGHOUT / ESU R Free: 0.569 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29496 1685 4.9 %RANDOM
Rwork0.24324 ---
obs0.24586 32550 47.79 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 81.832 Å2
Baniso -1Baniso -2Baniso -3
1--8.11 Å20 Å20 Å2
2--18.12 Å20 Å2
3----10 Å2
Refinement stepCycle: LAST / Resolution: 2.43→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11926 0 206 0 12132
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.02112502
X-RAY DIFFRACTIONr_bond_other_d0.0010.0210679
X-RAY DIFFRACTIONr_angle_refined_deg1.331.93917025
X-RAY DIFFRACTIONr_angle_other_deg0.755324841
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.86251454
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.23123.961616
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.521151994
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6781560
X-RAY DIFFRACTIONr_chiral_restr0.0720.21814
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213780
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022680
X-RAY DIFFRACTIONr_nbd_refined0.2440.62689
X-RAY DIFFRACTIONr_nbd_other0.2420.611069
X-RAY DIFFRACTIONr_nbtor_refined0.2040.55979
X-RAY DIFFRACTIONr_nbtor_other0.10.56763
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2030.5518
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0810.511
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.4440.629
X-RAY DIFFRACTIONr_symmetry_vdw_other0.4350.669
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0920.53
X-RAY DIFFRACTIONr_mcbond_it0.5551.59275
X-RAY DIFFRACTIONr_mcbond_other0.081.52942
X-RAY DIFFRACTIONr_mcangle_it0.653211766
X-RAY DIFFRACTIONr_scbond_it0.93536457
X-RAY DIFFRACTIONr_scangle_it1.5034.55259
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 11216 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
tight positional0.040.05
tight thermal0.10.5
LS refinement shellResolution: 2.43→2.49 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.427 27 -
Rwork0.335 662 -
obs-662 13.15 %
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)
10.6411-0.1158-0.23360.4405-0.26631.40980.03840.05830.0852-0.0656-0.0075-0.00860.05460.0303-0.0309-0.0753-0.0795-0.0186-0.17050.0637-0.019616.903615.608727.5595
20.58540.0262-0.14120.4755-0.24951.1932-0.0824-0.0056-0.00410.00430.08340.01050.0937-0.0798-0.001-0.0909-0.02560.0268-0.20780.0258-0.03510.0575-4.044677.8037
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A39 - 766
2X-RAY DIFFRACTION2B39 - 766

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