2XBA

Structure of Human Anaplastic Lymphoma Kinase in complex with PHA- E429


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 

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This is version 1.2 of the entry. See complete history


Literature

Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors.

Bossi, R.T.Saccardo, M.B.Ardini, E.Menichincheri, M.Rusconi, L.Magnaghi, P.Orsini, P.Avanzi, N.Borgia, A.L.Nesi, M.Bandiera, T.Fogliatto, G.Bertrand, J.A.

(2010) Biochemistry 49: 6813

  • DOI: https://doi.org/10.1021/bi1005514
  • Primary Citation of Related Structures:  
    2XB7, 2XBA

  • PubMed Abstract: 

    Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the development of several human cancers and, as a result, is a recognized target for the development of small-molecule inhibitors for the treatment of ALK-positive malignancies. Here, we present the crystal structures of the unphosphorylated human ALK kinase domain in complex with the ATP competitive ligands PHA-E429 and NVP-TAE684. Analysis of these structures provides valuable information concerning the specific characteristics of the ALK active site as well as giving indications about how to obtain selective ALK inhibitors. In addition, the ALK-KD-PHA-E429 structure led to the identification of a potential regulatory mechanism involving a link made between a short helical segment immediately following the DFG motif and an N-terminal two-stranded beta-sheet. Finally, mapping of the activating mutations associated with neuroblastoma onto our structures may explain the roles these residues have in the activation process.


  • Organizational Affiliation

    Nerviano Medical Sciences S.r.l., Viale Pasteur 10, 20014 Nerviano (MI), Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ALK TYROSINE KINASE RECEPTOR315Homo sapiensMutation(s): 0 
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UM73 (Homo sapiens)
Explore Q9UM73 
Go to UniProtKB:  Q9UM73
PHAROS:  Q9UM73
GTEx:  ENSG00000171094 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UM73
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
571
Query on 571

Download Ideal Coordinates CCD File 
B [auth A]5-[(2R)-2-hydroxy-2-phenylacetyl]-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-1,6-dihydropyrrolo[3,4-c]pyrazol-5-ium
C25 H27 N6 O3
FCLFBDYOCRVSHV-JOCHJYFZSA-O
Binding Affinity Annotations 
IDSourceBinding Affinity
571 PDBBind:  2XBA Ki: 23.68 (nM) from 1 assay(s)
Binding MOAD:  2XBA Ki: 23.68 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.884α = 90
b = 57.013β = 90
c = 105.541γ = 90
Software Package:
Software NamePurpose
CNXrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-07-28
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance