5L0E

Crystal Structure of Autotaxin and Compound 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.06 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.183 

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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design.

Jones, S.B.Pfeifer, L.A.Bleisch, T.J.Beauchamp, T.J.Durbin, J.D.Klimkowski, V.J.Hughes, N.E.Rito, C.J.Dao, Y.Gruber, J.M.Bui, H.Chambers, M.G.Chandrasekhar, S.Lin, C.McCann, D.J.Mudra, D.R.Oskins, J.L.Swearingen, C.A.Thirunavukkarasu, K.Norman, B.H.

(2016) ACS Med Chem Lett 7: 857-861

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00207
  • Primary Citation of Related Structures:  
    5L0B, 5L0E, 5L0K

  • PubMed Abstract: 

    In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.


  • Organizational Affiliation

    Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
A, B
871Rattus 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-(1-2)-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)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
D
6N-Glycosylation
Glycosylation Resources
GlyTouCan:  G47410OF
GlyCosmos:  G47410OF
GlyGen:  G47410OF
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6ZN
Query on 6ZN

Download Ideal Coordinates CCD File 
F [auth A],
L [auth B]
6-(3-{2-[(2,3-dihydro-1H-inden-2-yl)amino]-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl}propanoyl)-1,3-benzoxazol-2(3H)-one
C26 H25 N5 O3
XQEZVPRVJMIIGM-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
E [auth A],
K [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
H [auth A]
I [auth A]
J [auth A]
M [auth B]
N [auth B]
H [auth A],
I [auth A],
J [auth A],
M [auth B],
N [auth B],
O [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
G [auth A],
P [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.06 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.183 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 184.175α = 90
b = 96.838β = 112.82
c = 136.917γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
BUSTERrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Cootmodel building

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-08-10 
  • Deposition Author(s): Durbin, J.D.

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-10
    Type: Initial release
  • Version 1.1: 2016-10-05
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary