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

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Basic information

Entry
Database: PDB / ID: 5mhp
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 / positive regulation of peptidyl-tyrosine phosphorylation / scavenger receptor activity / 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-7NB / IODIDE ION / PHOSPHATE ION / THIOCYANATE ION / Autotaxin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsFleury, D. / Mueller, I. / Lamers, M. / Triballeau, N. / Mollat, P. / Vercheval, L.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a ...Title: Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis.
Authors: Desroy, N. / Housseman, C. / Bock, X. / Joncour, A. / Bienvenu, N. / Cherel, L. / Labeguere, V. / Rondet, E. / Peixoto, C. / Grassot, J.M. / Picolet, O. / Annoot, D. / Triballeau, N. / ...Authors: Desroy, N. / Housseman, C. / Bock, X. / Joncour, A. / Bienvenu, N. / Cherel, L. / Labeguere, V. / Rondet, E. / Peixoto, C. / Grassot, J.M. / Picolet, O. / Annoot, D. / Triballeau, N. / Monjardet, A. / Wakselman, E. / Roncoroni, V. / Le Tallec, S. / Blanque, R. / Cottereaux, C. / Vandervoort, N. / Christophe, T. / Mollat, P. / Lamers, M. / Auberval, M. / Hrvacic, B. / Ralic, J. / Oste, L. / van der Aar, E. / Brys, R. / Heckmann, B.
History
DepositionNov 25, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 30, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_strain
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 / 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 / pdbx_struct_mod_residue / 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.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.value / _pdbx_struct_mod_residue.auth_asym_id / _pdbx_struct_mod_residue.auth_seq_id / _pdbx_struct_mod_residue.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 2.1Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / 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_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
Revision 2.2Nov 13, 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: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,84515
Polymers100,1241
Non-polymers2,72114
Water2,882160
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4150 Å2
ΔGint-86 kcal/mol
Surface area30950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.230, 79.530, 79.740
Angle α, β, γ (deg.)90.00, 100.78, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 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 line (production host): HEK293 / Organ (production host): kidney / Production host: Homo sapiens (human) / Tissue (production host): embryonic
References: UniProt: Q13822, alkylglycerophosphoethanolamine phosphodiesterase

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Sugars , 2 types, 2 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]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: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-6]DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3/a4-b1_b4-c1_c6-d1_d3-e1_d6-g1_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]{}}[(6+1)][a-D-Manp]{}}}}}}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.: 1
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

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Non-polymers , 9 types, 172 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: Zn
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Ca
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Mg
#7: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#8: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#9: Chemical ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CNS
#10: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#11: Chemical ChemComp-7NB / 2-[[2-ethyl-8-methyl-6-[4-[2-(3-oxidanylazetidin-1-yl)-2-oxidanylidene-ethyl]piperazin-1-yl]imidazo[1,2-a]pyridin-3-yl]-methyl-amino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile


Mass: 588.699 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H33FN8O2S
#12: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 160 / 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: 48.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: PEG 3350 15%, thiocyanate 0.4 M and ammonium iodide 0.1 M

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 12, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.43→79.53 Å / Num. obs: 35498 / % possible obs: 98.8 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.075 / Net I/σ(I): 10.5
Reflection shellResolution: 2.43→2.49 Å / Redundancy: 3 % / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 1.9 / % possible all: 96.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5M7M

5m7m


Resolution: 2.43→75.87 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.912 / SU B: 9.296 / SU ML: 0.204 / Cross valid method: THROUGHOUT / ESU R: 0.454 / ESU R Free: 0.265 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24473 1778 5 %RANDOM
Rwork0.20671 ---
obs0.20866 33705 98.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.347 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å2-0 Å2-0.07 Å2
2--0 Å20 Å2
3---0.07 Å2
Refinement stepCycle: 1 / Resolution: 2.43→75.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6062 0 160 160 6382
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0196426
X-RAY DIFFRACTIONr_bond_other_d0.0010.025713
X-RAY DIFFRACTIONr_angle_refined_deg1.2161.9598743
X-RAY DIFFRACTIONr_angle_other_deg0.9062.98913180
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1515765
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.6223.16288
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.00915959
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.9221538
X-RAY DIFFRACTIONr_chiral_restr0.0680.2950
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0217153
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021515
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_it1.434.2643073
X-RAY DIFFRACTIONr_mcbond_other1.4294.2643074
X-RAY DIFFRACTIONr_mcangle_it2.4236.3873830
X-RAY DIFFRACTIONr_mcangle_other2.4236.3873831
X-RAY DIFFRACTIONr_scbond_it1.5474.2823353
X-RAY DIFFRACTIONr_scbond_other1.5474.2823354
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.4496.3624911
X-RAY DIFFRACTIONr_long_range_B_refined4.33133.5187073
X-RAY DIFFRACTIONr_long_range_B_other4.33133.5197074
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.43→2.493 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.427 107 -
Rwork0.409 2464 -
obs--96.69 %

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