5P9L

BTK1 IN COMPLEX WITH CC 292


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.25 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.265 
  • R-Value Observed: 0.266 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Ability of Bruton's Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling.

Bender, A.T.Gardberg, A.Pereira, A.Johnson, T.Wu, Y.Grenningloh, R.Head, J.Morandi, F.Haselmayer, P.Liu-Bujalski, L.

(2017) Mol Pharmacol 91: 208-219

  • DOI: https://doi.org/10.1124/mol.116.107037
  • Primary Citation of Related Structures:  
    5P9F, 5P9G, 5P9H, 5P9I, 5P9J, 5P9K, 5P9L, 5P9M

  • PubMed Abstract: 

    Bruton's tyrosine kinase (Btk) is expressed in a variety of hematopoietic cells. Btk has been demonstrated to regulate signaling downstream of the B-cell receptor (BCR), Fc receptors (FcRs), and toll-like receptors. It has become an attractive drug target because its inhibition may provide significant efficacy by simultaneously blocking multiple disease mechanisms. Consequently, a large number of Btk inhibitors have been developed. These compounds have diverse binding modes, and both reversible and irreversible inhibitors have been developed. Reported herein, we have tested nine Btk inhibitors and characterized on a molecular level how their interactions with Btk define their ability to block different signaling pathways. By solving the crystal structures of Btk inhibitors bound to the enzyme, we discovered that the compounds can be classified by their ability to trigger sequestration of Btk residue Y551. In cells, we found that sequestration of Y551 renders it inaccessible for phosphorylation. The ability to sequester Y551 was an important determinant of potency against FcεR signaling as Y551 sequestering compounds were more potent for inhibiting basophils and mast cells. This result was true for the inhibition of FcγR signaling as well. In contrast, Y551 sequestration was less a factor in determining potency against BCR signaling. We also found that Btk activity is regulated differentially in basophils and B cells. These results elucidate important determinants for Btk inhibitor potency against different signaling pathways and provide insight for designing new compounds with a broader inhibitory profile that will likely result in greater efficacy.


  • Organizational Affiliation

    TIP Immunology (A.T.B., A.P., Y.W., R.G.) and Discovery Technologies (A.G., T.J., J.H., F.M., L.L.-B.), EMD Serono Research and Development Institute, Billerica, Massachusetts; and TIP Immunology, Merck, Darmstadt, Germany (P.H.) andrew.bender@emdserono.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase BTK279Homo sapiensMutation(s): 0 
Gene Names: BTKAGMX1ATKBPK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q06187 (Homo sapiens)
Explore Q06187 
Go to UniProtKB:  Q06187
PHAROS:  Q06187
GTEx:  ENSG00000010671 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ06187
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7G9
Query on 7G9

Download Ideal Coordinates CCD File 
B [auth A]~{N}-[3-[[5-fluoranyl-2-[[4-(2-methoxyethoxy)phenyl]amino]pyrimidin-4-yl]amino]phenyl]propanamide
C22 H24 F N5 O3
PGJVJMYAHWTULI-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.25 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.265 
  • R-Value Observed: 0.266 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.022α = 90
b = 104.681β = 90
c = 38.311γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XSCALEdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-24
    Type: Initial release
  • Version 1.1: 2018-02-21
    Changes: Structure summary
  • Version 1.2: 2021-11-17
    Changes: Data collection, Database references, Structure summary