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- PDB-7mfh: Crystal structure of BIO-32546 bound mouse Autotaxin -

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Basic information

Entry
Database: PDB / ID: 7mfh
TitleCrystal structure of BIO-32546 bound mouse Autotaxin
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase family member 2
KeywordsHYDROLASE/INHIBITOR / hydrolase inhibitor / Autotaxin / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


dinucleotide phosphatase activity / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipid catabolic process / phosphatidylcholine catabolic process / lysophospholipase activity / positive regulation of lamellipodium morphogenesis / phosphodiesterase I activity / scavenger receptor activity / alkylglycerophosphoethanolamine phosphodiesterase activity ...dinucleotide phosphatase activity / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipid catabolic process / phosphatidylcholine catabolic process / lysophospholipase activity / positive regulation of lamellipodium morphogenesis / phosphodiesterase I activity / scavenger receptor activity / alkylglycerophosphoethanolamine phosphodiesterase activity / polysaccharide binding / positive regulation of oligodendrocyte differentiation / negative regulation of cell-matrix adhesion / positive regulation of epithelial cell migration / 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 / positive regulation of peptidyl-tyrosine phosphorylation / nucleic acid binding / immune response / calcium ion binding / positive regulation of cell population proliferation / 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
IODIDE ION / DI(HYDROXYETHYL)ETHER / Chem-ZF7 / Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsChodaparambil, J.V.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Discovery of Potent Selective Nonzinc Binding Autotaxin Inhibitor BIO-32546.
Authors: Ma, B. / Zhang, L. / Sun, L. / Xin, Z. / Kumaravel, G. / Marcotte, D. / Chodaparambil, J.V. / Wang, Q. / Wehr, A. / Jing, J. / Hong, V.S. / Wang, T. / Huang, C. / Shao, Z. / Mi, S.
History
DepositionApr 9, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 13, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)99,44527
Polymers95,8451
Non-polymers3,60126
Water3,099172
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.020, 61.620, 67.320
Angle α, β, γ (deg.)89.071, 74.202, 79.877
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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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: 95844.508 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Enpp2, Npps2, Pdnp2
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: Q9R1E6, 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)-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
#3: 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.: 1
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

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Non-polymers , 6 types, 196 molecules

#4: Chemical ChemComp-ZF7 / (1R,3S,5S)-8-{(1S)-1-[8-(trifluoromethyl)-7-{[(1s,4R)-4-(trifluoromethyl)cyclohexyl]oxy}naphthalen-2-yl]ethyl}-8-azabicyclo[3.2.1]octane-3-carboxylic acid / BIO-32546


Mass: 543.541 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H31F6NO3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Zn
#8: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 2.58 Å3/Da / Density % sol: 0.52 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop
Details: 0.2M ammonium iodide, 0.1M sodium iodide, 28% PEG3350

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Mar 27, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.3→46.13 Å / Num. obs: 40464 / % possible obs: 98 % / Redundancy: 2.7 % / Biso Wilson estimate: 45.8 Å2 / CC1/2: 0.99 / CC star: 0.99 / Rmerge(I) obs: 0.08 / Net I/σ(I): 7.7
Reflection shellResolution: 2.3→2.38 Å / Rmerge(I) obs: 0.88 / Num. unique obs: 4035 / CC1/2: 0.56

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3nkm

3nkm


Resolution: 2.3→46.13 Å / SU ML: 0.358 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 32.8948
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.268 2024 5 %
Rwork0.2149 38436 -
obs0.2176 40460 97.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60.22 Å2
Refinement stepCycle: LAST / Resolution: 2.3→46.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6237 0 209 172 6618
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00296605
X-RAY DIFFRACTIONf_angle_d0.60638944
X-RAY DIFFRACTIONf_chiral_restr0.044967
X-RAY DIFFRACTIONf_plane_restr0.00511142
X-RAY DIFFRACTIONf_dihedral_angle_d7.6479973
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.360.40611450.35592756X-RAY DIFFRACTION96.7
2.36-2.420.39861420.32792688X-RAY DIFFRACTION97.52
2.42-2.490.35851450.31922760X-RAY DIFFRACTION97.35
2.49-2.570.36311430.2912728X-RAY DIFFRACTION97.85
2.57-2.660.38371440.26472733X-RAY DIFFRACTION97.82
2.66-2.770.28431470.24672776X-RAY DIFFRACTION98.12
2.77-2.90.28831430.23882723X-RAY DIFFRACTION98.05
2.9-3.050.29551450.24732760X-RAY DIFFRACTION98.11
3.05-3.240.30021460.23682765X-RAY DIFFRACTION98.28
3.24-3.490.26171430.20192725X-RAY DIFFRACTION98.22
3.49-3.840.25541460.2042765X-RAY DIFFRACTION98.34
3.84-4.40.21421450.17312761X-RAY DIFFRACTION98.44
4.4-5.540.21621460.1742765X-RAY DIFFRACTION98.64
5.54-46.130.25241440.19552731X-RAY DIFFRACTION97.92
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)
11.89915773012-0.110675972485-0.2020044209472.53445301599-0.03765623905041.804558194780.07262464755280.1417601880.188256958121-0.211856704244-0.108421498749-0.334791403318-0.2620307811480.1500639191130.04807791860310.36986543147-0.03212741580340.1153790559440.338976963935-0.02336435381810.504197121902-2.8676818021944.3101184192-41.623334981
22.82787366818-0.344324149381-0.2168972850363.29644254789-1.904983680392.631057724490.09907036064220.232062914557-0.3095866827970.2093722758140.1819265460440.8867466040260.237503232337-0.727761435964-0.3097304759390.421083257417-0.02009859307490.1336594573140.641389866357-0.1300882011160.863972880693-39.834849865517.6610232203-1.26545940359
30.693129645858-0.074763100826-0.1026697415932.1773521359-1.61851104482.518511513740.0220971322682-0.178901924246-0.1060295586420.282325707836-0.152814376845-0.154123924013-0.05227015367640.1291666104450.1769829927920.385823845231-0.06422976012540.05188940723490.377153380097-0.07749277335830.51239729565-19.342921858223.8427895848-5.11997877304
40.723018985470.174455126999-0.3322635555693.86132343899-1.646006618941.80846177990.141522463352-0.1260779783660.1663938077080.447690782351-0.09232823436610.0430754013661-0.4728053522950.0383035601539-0.05996104843670.360007279958-0.04354647958170.03847060106810.353647583269-0.09959137025020.430720616434-19.89188504541.2568096234-12.641393635
51.538924913180.374824931718-0.9295214518581.05243053913-1.021053255893.70289449249-0.04800609222920.151137263742-0.249267219186-0.358300651551-0.218660339771-0.3410360538190.1566197893260.3026176115810.2323827222610.4389304788020.04003385917580.1202303684280.348931617839-0.0796485034780.616663848834-3.2578208181730.3887488178-38.5279286682
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 646 through 859 )646 - 859563 - 776
22chain 'A' and (resid 51 through 93 )51 - 931 - 42
33chain 'A' and (resid 94 through 280 )94 - 28043 - 229
44chain 'A' and (resid 281 through 483 )281 - 483230 - 422
55chain 'A' and (resid 484 through 645 )484 - 645423 - 562

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