PDBsum entry 2zva

Transferase

PDB id: 2zva

Contents

Protein chain

261 a.a. *

Ligands

1N1

Waters ×38

* Residue conservation analysis

PDB id:

2zva

Name:

Transferase

Title:

Lyn tyrosine kinase domain-dasatinib complex

Structure:

Tyrosine-protein kinase lyn. Chain: a. Fragment: kinase domain, residues 239-512. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.60Å R-factor: 0.199 R-free: 0.231

Authors:

N.K.Williams,J.Rossjohn

Key ref:

N.K.Williams et al. (2009). Crystal structures of the Lyn protein tyrosine kinase domain in its Apo- and inhibitor-bound state. J Biol Chem, 284, 284-291. PubMed id: 18984583 DOI: 10.1074/jbc.M807850200

Date:

04-Nov-08 Release date: 11-Nov-08

Protein chain

P25911  (LYN_MOUSE) -  Tyrosine-protein kinase Lyn from Mus musculus

Seq: 512 a.a.

Struc: 261 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.M807850200

J Biol Chem 284:284-291 (2009)

PubMed id: 18984583

Crystal structures of the Lyn protein tyrosine kinase domain in its Apo- and inhibitor-bound state.

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

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.

Selected figure(s)

Figure 2.
Overview of the crystal structure of Lyn. A, ribbon representation of the crystal structure of Lyn PTK. The N-terminal lobe (residues 239–326) shown in gray comprises a five-stranded anti-parallel β-sheet and one α-helix (αC). The C-terminal lobe (residues 327–501) is shown in green. The glycine loop is colored in orange, the hinge region between the two lobes in yellow, the catalytic loop in blue, and the activation loop in red. B, close-up of portions of the αC helix and activation loop showing active (Lyn (blue), Lck (yellow)) and inactive (Src (magenta), Hck (green)) conformations.

Figure 3.
Mode of inhibitors binding to Lyn PTK. A, interaction between AMP-PNP and Lyn PTK. B, interaction between PP2 and Lyn PTK. C, interaction between Dasatinib and Lyn PTK. Left panel, the side chains of residues that interact with the inhibitor are shown, as are main-chain atoms and water molecules participating in hydrogen bonds. Right panel, corresponding view of the inhibitor in a ball-and-stick representation and covered with the simulated annealing omit-map Fo-Fc electron density map contoured at 2σ.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2009, 284, 284-291) copyright 2009.

Figures were selected by an automated process.