2ZVA

Lyn Tyrosine Kinase Domain-Dasatinib complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.199 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Crystal Structures of the Lyn Protein Tyrosine Kinase Domain in Its Apo- and Inhibitor-bound State

Williams, N.K.Lucet, I.S.Klinken, S.P.Ingley, E.Rossjohn, J.

(2009) J Biol Chem 284: 284-291

  • DOI: https://doi.org/10.1074/jbc.M807850200
  • Primary Citation of Related Structures:  
    2ZV7, 2ZV8, 2ZV9, 2ZVA

  • PubMed Abstract: 

    The Src-family protein-tyrosine kinase (PTK) Lyn is the most important Src-family kinase in B cells, having both inhibitory and stimulatory activity that is dependent on the receptor, ligand, and developmental context of the B cell. An important role for Lyn has been reported in acute myeloid leukemia and chronic myeloid leukemia, as well as certain solid tumors. Although several Src-family inhibitors are available, the development of Lyn-specific inhibitors, or inhibitors with reduced off-target activity to Lyn, has been hampered by the lack of structural data on the Lyn kinase. Here we report the crystal structure of the non-liganded form of Lyn kinase domain, as well as in complex with three different inhibitors: the ATP analogue AMP-PNP; the pan Src kinase inhibitor PP2; and the BCR-Abl/Src-family inhibitor Dasatinib. The Lyn kinase domain was determined in its "active" conformation, but in the unphosphorylated state. All three inhibitors are bound at the ATP-binding site, with PP2 and Dasatinib extending into a hydrophobic pocket deep in the substrate cleft, thereby providing a basis for the Src-specific inhibition. Analysis of sequence and structural differences around the active site region of the Src-family PTKs were evident. Accordingly, our data provide valuable information for the further development of therapeutics targeting Lyn and the important Src-family of kinases.


  • Organizational Affiliation

    Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia, and the Laboratory for Cancer Medicine and Cell Signalling Group, Western Australian Institute for Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Western Australia 6000, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase Lyn279Mus musculusMutation(s): 0 
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P25911 (Mus musculus)
Explore P25911 
Go to UniProtKB:  P25911
IMPC:  MGI:96892
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25911
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1N1
Query on 1N1

Download Ideal Coordinates CCD File 
B [auth A]N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE
C22 H26 Cl N7 O2 S
ZBNZXTGUTAYRHI-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1N1 BindingDB:  2ZVA Kd: 0.57 (nM) from 1 assay(s)
IC50: min: 1.2, max: 10 (nM) from 2 assay(s)
PDBBind:  2ZVA IC50: 11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.199 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 127.378α = 90
b = 127.378β = 90
c = 55.619γ = 120
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-11-11
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description