5M0E

Structure-based evolution of a hybrid steroid series of Autotaxin inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators.

Keune, W.J.Potjewyd, F.Heidebrecht, T.Salgado-Polo, F.Macdonald, S.J.Chelvarajan, L.Abdel Latif, A.Soman, S.Morris, A.J.Watson, A.J.Jamieson, C.Perrakis, A.

(2017) J Med Chem 60: 2006-2017

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01743
  • Primary Citation of Related Structures:  
    5M0D, 5M0E, 5M0M, 5M0S

  • PubMed Abstract: 

    Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.


  • Organizational Affiliation

    Division of Biochemistry, The Netherlands Cancer Institute , Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ectonucleotide pyrophosphatase/phosphodiesterase family member 2827Rattus norvegicusMutation(s): 4 
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

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Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G15407YE
GlyCosmos:  G15407YE
GlyGen:  G15407YE
Small Molecules
Ligands 8 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7CR
Query on 7CR

Download Ideal Coordinates CCD File 
U [auth A][3,5-bis(chloranyl)phenyl]methyl 4-[(3~{R})-3-oxidanyl-3-(2-oxidanylidene-3~{H}-1,3-benzoxazol-6-yl)propyl]piperazine-1-carboxylate
C22 H23 Cl2 N3 O5
JESONUJDGUUYLO-LJQANCHMSA-N
5JK
Query on 5JK

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T [auth A]7alpha-hydroxycholesterol
C27 H46 O2
OYXZMSRRJOYLLO-RVOWOUOISA-N
IOD
Query on IOD

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E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
E [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],
P [auth A],
RA [auth A],
SA [auth A]
IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
GOL
Query on GOL

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MA [auth A],
NA [auth A],
OA [auth A],
PA [auth A],
QA [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
SCN
Query on SCN

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AA [auth A]
BA [auth A]
CA [auth A]
DA [auth A]
EA [auth A]
AA [auth A],
BA [auth A],
CA [auth A],
DA [auth A],
EA [auth A],
FA [auth A],
GA [auth A],
HA [auth A],
IA [auth A],
JA [auth A],
KA [auth A],
LA [auth A],
V [auth A],
W [auth A],
X [auth A],
Y [auth A],
Z [auth A]
THIOCYANATE ION
C N S
ZMZDMBWJUHKJPS-UHFFFAOYSA-M
CA
Query on CA

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Q [auth A]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
NA
Query on NA

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R [auth A],
S [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.618α = 103.43
b = 61.729β = 98.18
c = 63.696γ = 93.5
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-08-16
    Type: Initial release
  • Version 1.1: 2019-10-16
    Changes: Data collection
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2024-01-17
    Changes: Data collection, Database references, Refinement description, Structure summary