3MY0

Crystal structure of the ACVRL1 (ALK1) kinase domain bound to LDN-193189


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis.

Kerr, G.Sheldon, H.Chaikuad, A.Alfano, I.von Delft, F.Bullock, A.N.Harris, A.L.

(2015) Angiogenesis 18: 209-217

  • DOI: https://doi.org/10.1007/s10456-014-9457-y
  • Primary Citation of Related Structures:  
    3MY0

  • PubMed Abstract: 

    Activin receptor-like kinase 1 (ALK1, encoded by the gene ACVRL1) is a type I BMP/TGF-β receptor that mediates signalling in endothelial cells via phosphorylation of SMAD1/5/8. During angiogenesis, sprouting endothelial cells specialise into tip cells and stalk cells. ALK1 synergises with Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2 and thereby represses tip cell formation and angiogenic sprouting. The ALK1-Fc soluble protein fusion has entered clinic trials as a therapeutic strategy to sequester the high-affinity extracellular ligand BMP9. Here, we determined the crystal structure of the ALK1 intracellular kinase domain and explored the effects of a small molecule kinase inhibitor K02288 on angiogenesis. K02288 inhibited BMP9-induced phosphorylation of SMAD1/5/8 in human umbilical vein endothelial cells to reduce both the SMAD and the Notch-dependent transcriptional responses. In endothelial sprouting assays, K02288 treatment induced a hypersprouting phenotype reminiscent of Notch inhibition. Furthermore, K02288 caused dysfunctional vessel formation in a chick chorioallantoic membrane assay of angiogenesis. Such activity may be advantageous for small molecule inhibitors currently in preclinical development for specific BMP gain of function conditions, including diffuse intrinsic pontine glioma and fibrodysplasia ossificans progressiva, as well as more generally for other applications in tumour biology.


  • Organizational Affiliation

    Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase receptor R3
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X
305Homo sapiensMutation(s): 0 
Gene Names: ACVRL1ACVRL1 (ALK1)ACVRLK1ALK1
EC: 2.7.11.30
UniProt & NIH Common Fund Data Resources
Find proteins for P37023 (Homo sapiens)
Explore P37023 
Go to UniProtKB:  P37023
PHAROS:  P37023
GTEx:  ENSG00000139567 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP37023
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LDN
Query on LDN

Download Ideal Coordinates CCD File 
AA [auth C]
BA [auth D]
CA [auth E]
DA [auth F]
EA [auth G]
AA [auth C],
BA [auth D],
CA [auth E],
DA [auth F],
EA [auth G],
FA [auth H],
GA [auth I],
HA [auth J],
IA [auth K],
JA [auth L],
KA [auth M],
LA [auth N],
MA [auth O],
NA [auth P],
OA [auth Q],
PA [auth R],
QA [auth S],
RA [auth T],
SA [auth U],
TA [auth V],
UA [auth W],
VA [auth X],
Y [auth A],
Z [auth B]
4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline
C25 H22 N6
CDOVNWNANFFLFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
LDN BindingDB:  3MY0 IC50: min: 1.48, max: 13 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 
  • Space Group: P 32
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.77α = 90
b = 118.77β = 90
c = 510.791γ = 120
Software Package:
Software NamePurpose
PHASERphasing
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-07-21
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2015-04-01
    Changes: Database references
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description