5DLV

Crystal structure of Autotaxin (ENPP2) with tauroursodeoxycholic acid (TUDCA)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.

Keune, W.J.Hausmann, J.Bolier, R.Tolenaars, D.Kremer, A.Heidebrecht, T.Joosten, R.P.Sunkara, M.Morris, A.J.Matas-Rico, E.Moolenaar, W.H.Oude Elferink, R.P.Perrakis, A.

(2016) Nat Commun 7: 11248-11248

  • DOI: https://doi.org/10.1038/ncomms11248
  • Primary Citation of Related Structures:  
    5DLT, 5DLV, 5DLW

  • PubMed Abstract: 

    Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors of ATX, thereby attenuating LPA receptor activation. This unexpected interplay between ATX-LPA signalling and select steroids, notably natural bile salts, provides a molecular basis for the emerging association of ATX with disorders associated with increased circulating levels of bile salts. Furthermore, our findings suggest potential clinical implications in the use of steroid drugs.


  • Organizational Affiliation

    Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
A, B
827Rattus norvegicusMutation(s): 2 
Gene Names: c
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
Expand
  • 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-(1-2)-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
C
9N-Glycosylation
Glycosylation Resources
GlyTouCan:  G37135JQ
GlyCosmos:  G37135JQ
GlyGen:  G37135JQ
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-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
D
7N-Glycosylation
Glycosylation Resources
GlyTouCan:  G16404YH
GlyCosmos:  G16404YH
GlyGen:  G16404YH
Small Molecules
Ligands 8 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5D5
Query on 5D5

Download Ideal Coordinates CCD File 
AB [auth B],
Y [auth A]
2-{[(3alpha,5beta,7alpha,8alpha,14beta,17alpha)-3,7-dihydroxy-24-oxocholan-24-yl]amino}ethanesulfonic acid
C26 H45 N O6 S
BHTRKEVKTKCXOH-LBSADWJPSA-N
IOD
Query on IOD

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H [auth A]
I [auth A]
J [auth A]
K [auth A]
KA [auth B]
H [auth A],
I [auth A],
J [auth A],
K [auth A],
KA [auth B],
L [auth A],
LA [auth B],
M [auth A],
MA [auth B],
N [auth A],
NA [auth B],
O [auth A],
OA [auth B],
P [auth A],
PA [auth B],
Q [auth A],
QA [auth B],
R [auth A],
RA [auth B],
S [auth A],
SA [auth B],
T [auth A],
TA [auth B],
U [auth A],
UA [auth B],
VA [auth B],
WA [auth B]
IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
PO4
Query on PO4

Download Ideal Coordinates CCD File 
V [auth A],
XA [auth B]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL

Download Ideal Coordinates CCD File 
BA [auth A]
CA [auth A]
DA [auth A]
DB [auth B]
EA [auth A]
BA [auth A],
CA [auth A],
DA [auth A],
DB [auth B],
EA [auth A],
EB [auth B],
FA [auth A],
FB [auth B],
GA [auth A],
GB [auth B],
HB [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
HA [auth B],
IA [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
SCN
Query on SCN

Download Ideal Coordinates CCD File 
AA [auth A],
BB [auth B],
CB [auth B],
Z [auth A]
THIOCYANATE ION
C N S
ZMZDMBWJUHKJPS-UHFFFAOYSA-M
CA
Query on CA

Download Ideal Coordinates CCD File 
G [auth A],
JA [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
W [auth A],
X [auth A],
YA [auth B],
ZA [auth B]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5D5 Binding MOAD:  5DLV IC50: 1.04e+4 (nM) from 1 assay(s)
BindingDB:  5DLV IC50: 1.03e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.88α = 83.84
b = 77.832β = 79.29
c = 92.437γ = 77.08
Software Package:
Software NamePurpose
REFMACrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
Cootmodel building
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
NWONetherlands700.10.354
NWONetherlands723.013.003

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-13
    Type: Initial release
  • Version 1.1: 2016-04-27
    Changes: Database references
  • Version 1.2: 2018-02-14
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: 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