5LQQ

Structure of Autotaxin (ENPP2) with LM350


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.219 

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This is version 2.1 of the entry. See complete history


Literature

Structure-Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode.

Miller, L.M.Keune, W.J.Castagna, D.Young, L.C.Duffy, E.L.Potjewyd, F.Salgado-Polo, F.Engel Garcia, P.Semaan, D.Pritchard, J.M.Perrakis, A.Macdonald, S.J.Jamieson, C.Watson, A.J.

(2017) J Med Chem 60: 722-748

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01597
  • Primary Citation of Related Structures:  
    5LQQ

  • PubMed Abstract: 

    Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.


  • Organizational Affiliation

    WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ectonucleotide pyrophosphatase/phosphodiesterase family member 2827Rattus norvegicusMutation(s): 2 
Gene Names: Enpp2AtxNpps2
EC: 3.1.4.39
UniProt
Find proteins for Q64610 (Rattus norvegicus)
Explore Q64610 
Go to UniProtKB:  Q64610
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ64610
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
8N-Glycosylation
Glycosylation Resources
GlyTouCan:  G34499SX
GlyCosmos:  G34499SX
GlyGen:  G34499SX
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
72P
Query on 72P

Download Ideal Coordinates CCD File 
P [auth A]3-(6-chloranyl-2-methyl-1-phenyl-indol-3-yl)sulfanylbenzoic acid
C22 H16 Cl N O2 S
QESQUQBNRUZICQ-UHFFFAOYSA-N
IOD
Query on IOD

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
I [auth A]
J [auth A]
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A]
IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
E [auth A]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
Q [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
72P Binding MOAD:  5LQQ IC50: 81 (nM) from 1 assay(s)
BindingDB:  5LQQ IC50: min: 5, max: 300 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.219 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.655α = 90
b = 89.067β = 102.88
c = 77.509γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-12-28
    Type: Initial release
  • Version 1.1: 2017-01-18
    Changes: Database references
  • Version 1.2: 2017-02-08
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary