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- PDB-6w35: A new Autotaxin Inhibitor for the Treatment of Idiopathic Pulmona... -

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Basic information

Entry
Database: PDB / ID: 6w35
TitleA new Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase 2
KeywordsLIPID BINDING PROTEIN / autotaxin
Function / homology
Function and homology information


dinucleotide phosphatase activity / lysophospholipase activity / phosphodiesterase I activity / scavenger receptor activity / polysaccharide binding / regulation of angiogenesis / regulation of cell migration / chemotaxis / nucleic acid binding / membrane => GO:0016020 ...dinucleotide phosphatase activity / lysophospholipase activity / phosphodiesterase I activity / scavenger receptor activity / polysaccharide binding / regulation of angiogenesis / regulation of cell migration / chemotaxis / nucleic acid binding / membrane => GO:0016020 / immune response / extracellular region / metal ion binding
Similarity search - Function
Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 / 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 ...Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 / 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 / Alkaline-phosphatase-like, core domain superfamily
Similarity search - Domain/homology
IODIDE ION / THIOCYANATE ION / Chem-SKV / Ectonucleotide pyrophosphatase/phosphodiesterase 2
Similarity search - Component
Biological speciesPan troglodytes (chimpanzee)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.98 Å
AuthorsCuozzo, J.W.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry.
Authors: Cuozzo, J.W. / Clark, M.A. / Keefe, A.D. / Kohlmann, A. / Mulvihill, M. / Ni, H. / Renzetti, L.M. / Resnicow, D.I. / Ruebsam, F. / Sigel, E.A. / Thomson, H.A. / Wang, C. / Xie, Z. / Zhang, Y.
History
DepositionMar 9, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
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.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_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _chem_comp.name / _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 2.1Aug 5, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 2.2Oct 18, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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: Ectonucleotide pyrophosphatase/phosphodiesterase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,77530
Polymers94,2361
Non-polymers3,53929
Water9,332518
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.723, 77.377, 94.433
Angle α, β, γ (deg.)90.000, 112.110, 90.000
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 2


Mass: 94235.961 Da / Num. of mol.: 1 / Mutation: N298H,S552N,Q620E,I641V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Pan troglodytes (chimpanzee) / Gene: ENPP2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: K7CID1

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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 / N-Acetylglucosamine


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 , 8 types, 545 molecules

#4: Chemical ChemComp-SKV / 2-fluoranyl-~{N}-[(2~{R})-1-[1-(2~{H}-indazol-5-yl)-3-methyl-2,4-bis(oxidanylidene)-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxidanylidene-butan-2-yl]-5-(trifluoromethyl)benzamide


Mass: 588.553 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C28H28F4N6O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


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


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#7: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#8: Chemical ChemComp-SCN / THIOCYANATE ION / Thiocyanate


Mass: 58.082 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: CNS
#9: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Cl
#10: Chemical
ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: I
#11: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 518 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.84 Å3/Da / Density % sol: 56.67 % / Description: plate
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 17.50% (w/v) PEG 3350, 0.50 M NaSCN, 0.15 M NH4I

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99983 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99983 Å / Relative weight: 1
ReflectionResolution: 1.98→87.49 Å / Num. obs: 67503 / % possible obs: 95.6 % / Redundancy: 2.4 % / Biso Wilson estimate: 37.274 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.055 / Rrim(I) all: 0.07 / Χ2: 1.043 / Net I/σ(I): 12.86 / Num. measured all: 165354 / Scaling rejects: 43
Reflection shellResolution: 1.98→2.23 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.451 / Mean I/σ(I) obs: 2.43 / Num. measured obs: 48457 / Num. possible: 21035 / Num. unique obs: 20400 / CC1/2: 0.787 / Rrim(I) all: 0.024 / % possible all: 97

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MHP

5mhp


Resolution: 1.98→87.49 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.937 / SU B: 8.488 / SU ML: 0.125 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.156 / ESU R Free: 0.153
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2303 1928 2.9 %RANDOM
Rwork0.1786 ---
obs0.1801 65575 95.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 125.93 Å2 / Biso mean: 39.139 Å2 / Biso min: 17.93 Å2
Baniso -1Baniso -2Baniso -3
1--0.37 Å2-0 Å2-0.19 Å2
2---0.24 Å2-0 Å2
3---0.57 Å2
Refinement stepCycle: final / Resolution: 1.98→87.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6410 0 171 518 7099
Biso mean--37.58 40.05 -
Num. residues----792
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0196700
X-RAY DIFFRACTIONr_bond_other_d0.0020.026021
X-RAY DIFFRACTIONr_angle_refined_deg1.5951.9759087
X-RAY DIFFRACTIONr_angle_other_deg2.768313856
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4755789
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.68223.279308
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.28415.0241048
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9131542
X-RAY DIFFRACTIONr_chiral_restr0.1140.2982
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0217426
X-RAY DIFFRACTIONr_gen_planes_other0.0170.021565
LS refinement shellResolution: 1.98→2.031 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 141 -
Rwork0.288 4910 -
all-5051 -
obs--97.53 %
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)
11.2809-0.40520.15261.5553-0.64261.5080.0178-0.091-0.12210.0227-0.0723-0.23760.16090.27090.05460.03040.0127-0.02540.15720.01480.116919.357-1.45622.931
21.89250.07070.09251.1878-0.02240.8333-0.0037-0.07090.14260.03740.00770.2274-0.0627-0.1709-0.00390.010.0093-0.0080.1132-0.0160.1174-19.4969.13716.784
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 539
2X-RAY DIFFRACTION2A540 - 1000

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