PDBsum entry 3cd3

Transferase

PDB id: 3cd3

Contents

Protein chain

353 a.a. *

Ligands

ACE-ILE-TYR-GLU-SER-LEU

STU ×3

Metals

_CL ×2

Waters ×307

* Residue conservation analysis

PDB id:

3cd3

Name:

Transferase

Title:

Crystal structure of phosphorylated human feline sarcoma viral oncogene homologue (v-fes) in complex with staurosporine and a consensus peptide

Structure:

Proto-oncogene tyrosine-protein kinase fes/fps. Chain: a. Fragment: residues 448-822. Synonym: c-fes. Engineered: yes. Synthetic peptide. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fes, fps. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: synthetic peptide

Resolution:

1.98Å R-factor: 0.188 R-free: 0.247

Authors:

P.Filippakopoulos,E.Salah,C.Cooper,S.S.Picaud,J.M.Elkins,F.Von Delft, C.H.Arrowsmith,A.M.Edwards,J.Weigelt,C.Bountra,S.Knapp,Structural Genomics Consortium (Sgc)

Key ref:

P.Filippakopoulos et al. (2008). Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation. Cell, 134, 793-803. PubMed id: 18775312 DOI: 10.1016/j.cell.2008.07.047

Date:

26-Feb-08 Release date: 25-Mar-08

Protein chain

P07332  (FES_HUMAN) -  Tyrosine-protein kinase Fes/Fps from Homo sapiens

Seq: 822 a.a.

Struc: 353 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: 10.1016/j.cell.2008.07.047

Cell 134:793-803 (2008)

PubMed id: 18775312

Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.

P.Filippakopoulos, M.Kofler, O.Hantschel, G.D.Gish, F.Grebien, E.Salah, P.Neudecker, L.E.Kay, B.E.Turk, G.Superti-Furga, T.Pawson, S.Knapp.

ABSTRACT

The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase alphaC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.

Selected figure(s)

Figure 4.
Substrate Interaction with the Fes Kinase Domain (A) Details of the substrate peptide (IYESL) interaction with the kinase domain. (B) Structure of the Fes-substrate complex showing a detail of the location of the peptide (shown in sticks). The surface has been colored by electrostatic potential between [minus sign]10 and +10 kcal/mol. (C) 2F[o] -- F[c] electron density map contoured at 2[sigma] around the substrate peptide residues. Cell. 2008 September 5; 134(5): 793–803. doi: 10.1016/j.cell.2008.07.047. Copyright [copyright] 2008 ELL & Excerpta Medica

Figure 7.
Cartoon Representation of Fes Activation In its unligated and unphosphorylated state, the Fes SH2 domain (blue), [alpha]C (red), and activation segment (purple) are significantly disordered (left). Binding of a primed peptide (yellow) stabilizes the SH2 domain, leading to a productive orientation of the SH2 domain, with respect to the kinase domain, and stable positioning of [alpha]C (middle). Phosphorylation of the activation segment at Y713 and binding of the substrate molecule to the kinase domain stabilizes the activation segment in a conformation suitable for catalysis (right). Cell. 2008 September 5; 134(5): 793–803. doi: 10.1016/j.cell.2008.07.047. Copyright [copyright] 2008 ELL & Excerpta Medica

The above figures are reprinted from an Open Access publication published by Cell Press: Cell (2008, 134, 793-803) copyright 2008.

Figures were selected by an automated process.