3H9R

Crystal structure of the kinase domain of type I activin receptor (ACVR1) in complex with FKBP12 and dorsomorphin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure of the Bone Morphogenetic Protein Receptor ALK2 and Implications for Fibrodysplasia Ossificans Progressiva.

Chaikuad, A.Alfano, I.Kerr, G.Sanvitale, C.E.Boergermann, J.H.Triffitt, J.T.von Delft, F.Knapp, S.Knaus, P.Bullock, A.N.

(2012) J Biol Chem 287: 36990-36998

  • DOI: https://doi.org/10.1074/jbc.M112.365932
  • Primary Citation of Related Structures:  
    3H9R

  • PubMed Abstract: 

    Bone morphogenetic protein (BMP) receptor kinases are tightly regulated to control development and tissue homeostasis. Mutant receptor kinase domains escape regulation leading to severely degenerative diseases and represent an important therapeutic target. Fibrodysplasia ossificans progressiva (FOP) is a rare but devastating disorder of extraskeletal bone formation. FOP-associated mutations in the BMP receptor ALK2 reduce binding of the inhibitor FKBP12 and promote leaky signaling in the absence of ligand. To establish structural mechanisms of receptor regulation and to address the effects of FOP mutation, we determined the crystal structure of the cytoplasmic domain of ALK2 in complex with the inhibitors FKBP12 and dorsomorphin. FOP mutations break critical interactions that stabilize the inactive state of the kinase, thereby facilitating structural rearrangements that diminish FKBP12 binding and promote the correct positioning of the glycine-serine-rich loop and αC helix for kinase activation. The balance of these effects accounts for the comparable activity of R206H and L196P. Kinase activation in the clinically benign mutant L196P is far weaker than R206H but yields equivalent signals due to the stronger interaction of FKBP12 with R206H. The presented ALK2 structure offers a valuable template for the further design of specific inhibitors of BMP signaling.


  • Organizational Affiliation

    Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Activin receptor type-1330Homo sapiensMutation(s): 0 
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
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Peptidyl-prolyl cis-trans isomerase FKBP1A109Homo sapiensMutation(s): 0 
Gene Names: FKBP1FKBP12FKBP1A
EC: 5.2.1.8
UniProt & NIH Common Fund Data Resources
Find proteins for P62942 (Homo sapiens)
Explore P62942 
Go to UniProtKB:  P62942
PHAROS:  P62942
GTEx:  ENSG00000088832 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP62942
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TAK
Query on TAK

Download Ideal Coordinates CCD File 
C [auth A]6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine
C24 H25 N5 O
XHBVYDAKJHETMP-UHFFFAOYSA-N
PG4
Query on PG4

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
K [auth A]
TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
TAK BindingDB:  3H9R IC50: min: 9.76, max: 148.1 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.349α = 90
b = 62.345β = 90
c = 171.597γ = 90
Software Package:
Software NamePurpose
PHASERphasing
REFMACrefinement
MOSFLMdata 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: 2009-06-02
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2012-11-28
    Changes: Database references
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description