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- PDB-5m0e: Structure-based evolution of a hybrid steroid series of Autotaxin... -

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Basic information

Entry
Database: PDB / ID: 5m0e
TitleStructure-based evolution of a hybrid steroid series of Autotaxin inhibitors
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase family member 2
KeywordsHYDROLASE / medicinal chemistry / structure based design / autotaxin
Function / homology
Function and homology information


response to polycyclic arene / 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 ...response to polycyclic arene / 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 / alkylglycerophosphoethanolamine phosphodiesterase activity / cellular response to cadmium ion / polysaccharide binding / positive regulation of oligodendrocyte differentiation / positive regulation of epithelial cell migration / negative regulation of cell-matrix adhesion / positive regulation of focal adhesion assembly / estrous cycle / phospholipid metabolic process / positive regulation of substrate adhesion-dependent cell spreading / regulation of cell migration / cell chemotaxis / cellular response to estradiol stimulus / nucleic acid binding / immune response / positive regulation of cell population proliferation / calcium ion binding / extracellular space / zinc ion binding / membrane
Similarity search - Function
Extracellular Endonuclease; Chain A / 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 ...Extracellular Endonuclease; Chain A / 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 / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
7alpha-hydroxycholesterol / Chem-7CR / IODIDE ION / THIOCYANATE ION / Autotaxin
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsKeune, W.-J. / Heidebrecht, T. / Perrakis, A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators.
Authors: Keune, W.J. / Potjewyd, F. / Heidebrecht, T. / Salgado-Polo, F. / Macdonald, S.J. / Chelvarajan, L. / Abdel Latif, A. / Soman, S. / Morris, A.J. / Watson, A.J. / Jamieson, C. / Perrakis, A.
History
DepositionOct 4, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / 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 / 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 / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_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 / _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 / 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
Revision 2.2Nov 20, 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)99,94945
Polymers95,0381
Non-polymers4,91144
Water4,053225
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7050 Å2
ΔGint-75 kcal/mol
Surface area31490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.618, 61.729, 63.696
Angle α, β, γ (deg.)103.43, 98.18, 93.50
Int Tables number1
Space group name H-MP1

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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: 95037.656 Da / Num. of mol.: 1 / Mutation: N410A, L581F, R591T, N806A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Enpp2, Atx, Npps2 / Cell line (production host): Hek293 / Organ (production host): kidney / Production host: Homo sapiens (human)
References: UniProt: Q64610, alkylglycerophosphoethanolamine phosphodiesterase
#2: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE

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Non-polymers , 9 types, 268 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: I
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#7: Chemical ChemComp-5JK / 7alpha-hydroxycholesterol / (3beta,7alpha,9beta,14beta)-cholest-5-ene-3,7-diol


Mass: 402.653 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O2
#8: Chemical ChemComp-7CR / [3,5-bis(chloranyl)phenyl]methyl 4-[(3~{R})-3-oxidanyl-3-(2-oxidanylidene-3~{H}-1,3-benzoxazol-6-yl)propyl]piperazine-1-carboxylate


Mass: 480.341 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23Cl2N3O5
#9: Chemical
ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: CNS
#10: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 225 / 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: 2.13 Å3/Da / Density % sol: 42.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: PEG 3350, NaSCN and NH4I

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jun 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→61.15 Å / Num. obs: 53155 / % possible obs: 98.8 % / Redundancy: 3.9 % / Net I/σ(I): 18.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSv1.0data reduction
Aimlessv1.0data scaling
PHASERv1.0phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2XR9

2xr9


Resolution: 1.95→61.15 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.926 / SU B: 9.288 / SU ML: 0.127 / Cross valid method: THROUGHOUT / ESU R: 0.182 / ESU R Free: 0.158 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22295 2761 4.9 %RANDOM
Rwork0.18102 ---
obs0.18309 53155 97.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 28.509 Å2
Baniso -1Baniso -2Baniso -3
1--0.74 Å2-0.11 Å2-0.55 Å2
2--0.62 Å20.61 Å2
3----0.01 Å2
Refinement stepCycle: 1 / Resolution: 1.95→61.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6238 0 200 225 6663
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0196640
X-RAY DIFFRACTIONr_bond_other_d0.0020.026033
X-RAY DIFFRACTIONr_angle_refined_deg1.6311.9738992
X-RAY DIFFRACTIONr_angle_other_deg0.98313958
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7065777
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.62123.175315
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.276151070
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9231548
X-RAY DIFFRACTIONr_chiral_restr0.090.2949
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0217325
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021563
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_it1.0632.2113117
X-RAY DIFFRACTIONr_mcbond_other1.0462.1943098
X-RAY DIFFRACTIONr_mcangle_it1.7873.2813870
X-RAY DIFFRACTIONr_mcangle_other1.7873.2823871
X-RAY DIFFRACTIONr_scbond_it1.3072.4373523
X-RAY DIFFRACTIONr_scbond_other1.3072.4373523
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.1393.5645120
X-RAY DIFFRACTIONr_long_range_B_refined4.17926.0617550
X-RAY DIFFRACTIONr_long_range_B_other4.17926.0667551
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.95→2.001 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.268 207 -
Rwork0.271 3912 -
obs--96.64 %
Refinement TLS params.Method: refined / Origin x: -4.756 Å / Origin y: -45.621 Å / Origin z: 40.8326 Å
111213212223313233
T0.0033 Å2-0.0012 Å20.0021 Å2-0.0107 Å2-0.0045 Å2--0.0041 Å2
L0.4342 °20.0428 °20.2354 °2-0.4539 °20.1438 °2--0.4021 °2
S-0.0029 Å °0.0231 Å °-0.032 Å °0.0233 Å °0.0175 Å °-0.0011 Å °-0.0017 Å °-0.0181 Å °-0.0146 Å °

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