3MTF

Crystal structure of the ACVR1 kinase in complex with a 2-aminopyridine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.185 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A new class of small molecule inhibitor of BMP signaling.

Sanvitale, C.E.Kerr, G.Chaikuad, A.Ramel, M.C.Mohedas, A.H.Reichert, S.Wang, Y.Triffitt, J.T.Cuny, G.D.Yu, P.B.Hill, C.S.Bullock, A.N.

(2013) PLoS One 8: e62721-e62721

  • DOI: https://doi.org/10.1371/journal.pone.0062721
  • Primary Citation of Related Structures:  
    3MTF, 3Q4U

  • PubMed Abstract: 

    Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.


  • Organizational Affiliation

    Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Activin receptor type-1
A, B
301Homo sapiensMutation(s): 1 
Gene Names: ACVR1ACVRLK2
EC: 2.7.11.30
UniProt & NIH Common Fund Data Resources
Find proteins for Q04771 (Homo sapiens)
Explore Q04771 
Go to UniProtKB:  Q04771
PHAROS:  Q04771
GTEx:  ENSG00000115170 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ04771
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
A3F
Query on A3F

Download Ideal Coordinates CCD File 
CA [auth B],
Q [auth A]
3-[6-amino-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl]phenol
C20 H20 N2 O4
CJLMANFTWLNAKC-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
F [auth A]
R [auth B]
C [auth A],
D [auth A],
E [auth A],
F [auth A],
R [auth B],
S [auth B],
T [auth B],
U [auth B]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
G [auth A]
H [auth A]
I [auth A]
AA [auth B],
BA [auth B],
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],
V [auth B],
W [auth B],
X [auth B],
Y [auth B],
Z [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
A3F BindingDB:  3MTF IC50: min: 1.2, max: 420 (nM) from 5 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.185 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.688α = 90
b = 138.255β = 90
c = 59.934γ = 90
Software Package:
Software NamePurpose
PHASERphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-06-23
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2014-06-18
    Changes: Database references
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description