4ZG7

Structural basis for inhibition of human autotaxin by four novel compounds


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 

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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding.

Stein, A.J.Bain, G.Prodanovich, P.Santini, A.M.Darlington, J.Stelzer, N.M.Sidhu, R.S.Schaub, J.Goulet, L.Lonergan, D.Calderon, I.Evans, J.F.Hutchinson, J.H.

(2015) Mol Pharmacol 88: 982-992

  • DOI: https://doi.org/10.1124/mol.115.100404
  • Primary Citation of Related Structures:  
    4ZG6, 4ZG7, 4ZG9, 4ZGA

  • PubMed Abstract: 

    Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.


  • Organizational Affiliation

    Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ectonucleotide pyrophosphatase/phosphodiesterase family member 2806Homo sapiensMutation(s): 1 
Gene Names: ENPP2ATXPDNP2
EC: 3.1.4.39
UniProt & NIH Common Fund Data Resources
Find proteins for Q13822 (Homo sapiens)
Explore Q13822 
Go to UniProtKB:  Q13822
PHAROS:  Q13822
GTEx:  ENSG00000136960 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13822
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4O0
Query on 4O0

Download Ideal Coordinates CCD File 
H [auth A]3-({6-chloro-7-fluoro-2-methyl-1-[2-oxo-2-(spiro[cyclopropane-1,3'-indol]-1'(2'H)-yl)ethyl]-1H-indol-3-yl}sulfanyl)-2-fluorobenzoic acid
C28 H21 Cl F2 N2 O3 S
YFALJJNRFPFPRE-UHFFFAOYSA-N
NKN
Query on NKN

Download Ideal Coordinates CCD File 
I [auth A](2R)-2-hydroxy-3-(phosphonooxy)propyl tetradecanoate
C17 H35 O7 P
FAZBDRGXCKPVJU-MRXNPFEDSA-N
GOL
Query on GOL

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J [auth A]
K [auth A]
L [auth A]
M [auth A]
N [auth A]
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

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C [auth A],
D [auth A]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA

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E [auth A]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

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Q [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

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F [auth A],
G [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4O0 Binding MOAD:  4ZG7 IC50: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 61.77α = 90
b = 85.819β = 111.34
c = 83.855γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-10-14
    Type: Initial release
  • Version 1.1: 2015-11-11
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary