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- PDB-5m7m: Novel Imidazo[1,2-a]pyridine Derivatives with Potent Autotaxin/EN... -

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Basic information

Entry
Database: PDB / ID: 5m7m
TitleNovel Imidazo[1,2-a]pyridine Derivatives with Potent Autotaxin/ENPP2 Inhibitor Activity
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase family member 2
KeywordsHYDROLASE / ATX / Inhibitor / ENPP2
Function / homology
Function and homology information


Vitamin B5 (pantothenate) metabolism / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipase D / phospholipid catabolic process / phosphatidylcholine catabolic process / phospholipase D activity / positive regulation of lamellipodium morphogenesis / phosphodiesterase I activity / phosphatidylcholine lysophospholipase activity ...Vitamin B5 (pantothenate) metabolism / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipase D / phospholipid catabolic process / phosphatidylcholine catabolic process / phospholipase D activity / positive regulation of lamellipodium morphogenesis / phosphodiesterase I activity / phosphatidylcholine lysophospholipase activity / scavenger receptor activity / positive regulation of peptidyl-tyrosine phosphorylation / alkylglycerophosphoethanolamine phosphodiesterase activity / polysaccharide binding / positive regulation of epithelial cell migration / regulation of cell migration / cell motility / chemotaxis / nucleic acid binding / hydrolase activity / immune response / calcium ion binding / extracellular space / zinc ion binding / plasma membrane
Similarity search - Function
Somatomedin B domain, chordata / Somatomedin B -like domains / Somatomedin B domain / Somatomedin B-like domain superfamily / Somatomedin B domain / Somatomedin B domain (SMB) signature. / Somatomedin B (SMB) domain profile. / Type I phosphodiesterase/nucleotide pyrophosphatase/phosphate transferase / Type I phosphodiesterase / nucleotide pyrophosphatase / Extracellular Endonuclease, subunit A ...Somatomedin B domain, chordata / Somatomedin B -like domains / Somatomedin B domain / Somatomedin B-like domain superfamily / Somatomedin B domain / Somatomedin B domain (SMB) signature. / Somatomedin B (SMB) domain profile. / Type I phosphodiesterase/nucleotide pyrophosphatase/phosphate transferase / Type I phosphodiesterase / nucleotide pyrophosphatase / Extracellular Endonuclease, subunit A / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease superfamily / His-Me finger superfamily / Alkaline-phosphatase-like, core domain superfamily
Similarity search - Domain/homology
Chem-7HR / IODIDE ION / : / NICKEL (II) ION / PHOSPHATE ION / THIOCYANATE ION / Autotaxin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsWolhkoning, A. / Fleury, D. / Leonard, P. / Triballeau, N. / Mollat, P. / Vercheval, L.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors.
Authors: Joncour, A. / Desroy, N. / Housseman, C. / Bock, X. / Bienvenu, N. / Cherel, L. / Labeguere, V. / Peixoto, C. / Annoot, D. / Lepissier, L. / Heiermann, J. / Hengeveld, W.J. / Pilzak, G. / ...Authors: Joncour, A. / Desroy, N. / Housseman, C. / Bock, X. / Bienvenu, N. / Cherel, L. / Labeguere, V. / Peixoto, C. / Annoot, D. / Lepissier, L. / Heiermann, J. / Hengeveld, W.J. / Pilzak, G. / Monjardet, A. / Wakselman, E. / Roncoroni, V. / Le Tallec, S. / Galien, R. / David, C. / Vandervoort, N. / Christophe, T. / Conrath, K. / Jans, M. / Wohlkonig, A. / Soror, S. / Steyaert, J. / Touitou, R. / Fleury, D. / Vercheval, L. / Mollat, P. / Triballeau, N. / van der Aar, E. / Brys, R. / Heckmann, B.
History
DepositionOct 28, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 30, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 31, 2018Group: Database references / Category: pdbx_related_exp_data_set
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / diffrn_radiation_wavelength / 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_conn_angle / struct_asym / struct_conn / struct_conn_type / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _struct_conn.conn_type_id / _struct_conn.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_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn_type.id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 23, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,84420
Polymers100,1241
Non-polymers2,72019
Water95553
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4370 Å2
ΔGint-183 kcal/mol
Surface area29530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.450, 78.890, 78.570
Angle α, β, γ (deg.)90.00, 91.87, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 / E-NPP 2 / Autotaxin / Extracellular lysophospholipase D / LysoPLD


Mass: 100123.742 Da / Num. of mol.: 1 / Mutation: S493P
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ENPP2, ATX, PDNP2 / Plasmid: pTT5 / Cell (production host): epithelial / Cell line (production host): HEK293 / Organ (production host): kidney / Production host: Homo sapiens (human)
References: UniProt: Q13822, alkylglycerophosphoethanolamine phosphodiesterase
#2: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c6-d1_d3-e1_e2-f1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}}}}}}LINUCSPDB-CARE

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Non-polymers , 9 types, 71 molecules

#3: Chemical ChemComp-7HR / ~{N}-[6-[1-[3-(dimethylamino)propylsulfonyl]piperidin-4-yl]-2-ethyl-imidazo[1,2-a]pyridin-3-yl]-4-(4-fluorophenyl)-~{N}-methyl-1,3-thiazol-2-amine


Mass: 584.771 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C29H37FN6O2S2
#4: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: I
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: Cl
#6: Chemical ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CNS
#7: Chemical
ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Ni
#8: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#9: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#10: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 2.4 Å3/Da / Density % sol: 48.67 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: PEG3350 25%, 0.2M thiocyanate, 0.1M ammonium iodide

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.98011 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 9, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98011 Å / Relative weight: 1
ReflectionResolution: 2.7→78.89 Å / Num. obs: 26178 / % possible obs: 93.5 % / Redundancy: 2.7 % / CC1/2: 0.879 / Rmerge(I) obs: 0.164 / Net I/σ(I): 10.7
Reflection shellResolution: 2.7→2.77 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.626 / Mean I/σ(I) obs: 2.7 / CC1/2: 0.396 / % possible all: 95.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→78.53 Å / Cor.coef. Fo:Fc: 0.88 / Cor.coef. Fo:Fc free: 0.822 / SU B: 17.37 / SU ML: 0.347 / Cross valid method: THROUGHOUT / ESU R Free: 0.409 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28426 1278 5.3 %RANDOM
Rwork0.22896 ---
obs0.23193 23047 92.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 25.371 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20.11 Å2
2--0.03 Å20 Å2
3----0.05 Å2
Refinement stepCycle: 1 / Resolution: 2.7→78.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5811 0 135 53 5999
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0196131
X-RAY DIFFRACTIONr_bond_other_d0.0020.025385
X-RAY DIFFRACTIONr_angle_refined_deg1.5261.9698367
X-RAY DIFFRACTIONr_angle_other_deg0.953.00312334
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6995754
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.9123.035257
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.75715862
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2391534
X-RAY DIFFRACTIONr_chiral_restr0.0790.2918
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0216911
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021448
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4872.713032
X-RAY DIFFRACTIONr_mcbond_other1.4852.7093030
X-RAY DIFFRACTIONr_mcangle_it2.554.0553780
X-RAY DIFFRACTIONr_mcangle_other2.5494.0563781
X-RAY DIFFRACTIONr_scbond_it1.4712.6543099
X-RAY DIFFRACTIONr_scbond_other1.4632.6483095
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.3443.954581
X-RAY DIFFRACTIONr_long_range_B_refined4.61521.076882
X-RAY DIFFRACTIONr_long_range_B_other4.61521.0716883
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.356 93 -
Rwork0.335 1707 -
obs--94.64 %

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