6QAS

Crystal structure of ULK1 in complexed with PF-03814735

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2).

Chaikuad, A., Koschade, S.E., Stolz, A., Zivkovic, K., Pohl, C., Shaid, S., Ren, H., Lambert, L.J., Cosford, N.D.P., Brandts, C.H., Knapp, S.

(2019) Biochem J 476: 875-887

  • DOI: https://doi.org/10.1042/BCJ20190038
  • Primary Citation of Related Structures:  
    6QAS, 6QAT, 6QAU, 6QAV

  • PubMed Abstract: 

    Autophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 (Unc-51-like autophagy activating kinase 1) has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have been reported, little is known about the other closely related kinase ULK2 (Unc-51-like autophagy activating kinase 2). Here, we present the crystal structure of ULK2 in complex with ATP competitive inhibitors. Surprisingly, the ULK2 structure revealed a dimeric assembly reminiscent of dimeric arrangements of auto-activating kinases suggesting a role for this association in ULK activation. Screening of a kinase focused library of pre-clinical and clinical compounds revealed several potent ULK1/2 inhibitors and good correlation of inhibitor-binding behavior with both ULK kinases. Aurora A was identified as a major off-target of currently used ULK1 inhibitors. Autophagic flux assays demonstrated that this off-target activity by strongly inducing autophagy in different cellular systems conferred an additional layer of complexity in the interpretation of cellular data. The data presented here provide structural models and chemical starting points for the development of ULK1/2 dual inhibitors with improved selectivity for future exploitation of autophagy inhibition.

    • Organizational Affiliation: 

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt, Germany knapp@pharmchem.uni-frankfurt.de chaikuad@pharmchem.uni-frankfurt.de.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase ULK1
A, B
287Homo sapiensMutation(s): 0 
Gene Names: ULK1, KIAA0722
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O75385 (Homo sapiens)
Explore O75385 
Go to UniProtKB:  O75385
PHAROS:  O75385
GTEx:  ENSG00000177169 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO75385
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
34W
Query on 34W
Download Ideal Coordinates CCD File 
IA [auth B],
JA [auth B],
T [auth A]		N-{2-[(1S,4R)-6-{[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-1,2,3,4-tetrahydro-1,4-epiminonaphthalen-9-yl]-2-oxoethyl}acetamide
C23 H25 F3 N6 O2
RYYNGWLOYLRZLK-RBUKOAKNSA-N
CIT
Query on CIT
Download Ideal Coordinates CCD File 
F [auth A],
X [auth B]		CITRIC ACID
C6 H8 O7
KRKNYBCHXYNGOX-UHFFFAOYSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
U [auth B]
V [auth B]
C [auth A],
D [auth A],
E [auth A],
U [auth B],
V [auth B],
W [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL
Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
CA [auth B]
G [auth A]
H [auth A]
AA [auth B],
BA [auth B],
CA [auth B],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
Y [auth B],
Z [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO
Download Ideal Coordinates CCD File 
DA [auth B]
EA [auth B]
FA [auth B]
GA [auth B]
HA [auth B]
DA [auth B],
EA [auth B],
FA [auth B],
GA [auth B],
HA [auth B],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
Q [auth A],
R [auth A],
S [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A, B
L-PEPTIDE LINKINGC3 H8 N O6 PSER
TPO
Query on TPO
A, B
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.241α = 90
b = 74.241β = 90
c = 222.31γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-02-27
    Type: Initial release
  • Version 1.1: 2019-03-20
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description