PDBsum entry 3d7t

Transferase

PDB id: 3d7t

Contents

Protein chains

249 a.a. *

265 a.a. *

Ligands

STU ×2

* Residue conservation analysis

PDB id:

3d7t

Name:

Transferase

Title:

Structural basis for the recognition of c-src by its inactivator csk

Structure:

Tyrosine-protein kinase csk. Chain: a. Fragment: csk kinase domain. Synonym: c-src kinase, protein-tyrosine kinase cyl. Engineered: yes. Mutation: yes. Proto-oncogene tyrosine-protein kinase src. Chain: b. Fragment: c-src kinase domain.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csk. Expressed in: escherichia coli. Expression_system_taxid: 562. Gallus gallus. Chicken. Organism_taxid: 9031.

Resolution:

2.90Å R-factor: 0.239 R-free: 0.278

Authors:

N.M.Levinson,M.A.Seeliger,P.A.Cole,J.Kuriyan

Key ref:

N.M.Levinson et al. (2008). Structural basis for the recognition of c-Src by its inactivator Csk. Cell, 134, 124-134. PubMed id: 18614016 DOI: 10.1016/j.cell.2008.05.051

Date:

21-May-08 Release date: 05-Aug-08

Protein chain

P41240  (CSK_HUMAN) -  Tyrosine-protein kinase CSK from Homo sapiens

Seq: 450 a.a.

Struc: 249 a.a.*

Protein chain

P00523  (SRC_CHICK) -  Proto-oncogene tyrosine-protein kinase Src from Gallus gallus

Seq: 533 a.a.

Struc: 265 a.a.

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

Enzyme reactions

• Enzyme class: Chains A, B: 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: 10.1016/j.cell.2008.05.051

Cell 134:124-134 (2008)

PubMed id: 18614016

Structural basis for the recognition of c-Src by its inactivator Csk.

N.M.Levinson, M.A.Seeliger, P.A.Cole, J.Kuriyan.

ABSTRACT

The catalytic activity of the Src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the C terminus (Tyr 527 in c-Src), which is catalyzed by C-terminal Src Kinase (Csk). Given the promiscuity of most tyrosine kinases, it is remarkable that the C-terminal tails of the Src family kinases are the only known targets of Csk. We have determined the crystal structure of a complex between the kinase domains of Csk and c-Src at 2.9 A resolution, revealing that interactions between these kinases position the C-terminal tail of c-Src at the edge of the active site of Csk. Csk cannot phosphorylate substrates that lack this docking mechanism because the conventional substrate binding site used by most tyrosine kinases to recognize substrates is destabilized in Csk by a deletion in the activation loop.

Selected figure(s)

Figure 5.
Figure 5. Activation Loop Anchoring in Tyrosine Kinases
(A) The structure of the insulin receptor kinase domain (IRK) bound to a substrate peptide is shown. The panel on the right shows an enlarged view depicting the two anchor points and the loops to which they form hydrogen bonds (shown as dashed lines).
(B) The activation loops from 12 structures of active tyrosine kinases (see Experimental Procedures). The structures were aligned on the catalytic loops, but only the activation loops are shown.
(C) Hydrophobic interactions couple anchor point 2 to the peptide-binding site. The structure of IRK is shown. Residues of the substrate peptide that interact with the hydrophobic residues are indicated.

Figure 7.
Figure 7. The Inactive Assembled State of c-Src Is Incompatible with the Csk:c-Src Complex
(A) The crystal structure of inactive assembled c-Src (PDB code 2SRC) is aligned on the C-terminal lobe of c-Src from our Csk[KD]:c-Src[KD] structure. Clashes between the tail of inactive c-Src and the C lobe of Csk are highlighted in black.
(B) Csk cannot bind tail-phosphorylated c-Src as measured by surface plasmon resonance. A construct of c-Src that contains the SH2, SH3, and kinase domains (Src[3D]) was phosphorylated by Csk on Tyr 527 (Src[3D] pY527) prior to immobilization on the sensor surface. The binding of Csk[FL] (10 μM) to the surface was then measured. The graphs show the mean and standard deviation of two experiments.

The above figures are reprinted from an Open Access publication published by Cell Press: Cell (2008, 134, 124-134) copyright 2008.

Figures were selected by an automated process.