PDBsum entry 2i0v

Transferase

PDB id: 2i0v

Contents

Protein chain

303 a.a. *

Ligands

SO4

6C3

Waters ×26

* Residue conservation analysis

PDB id:

2i0v

Name:

Transferase

Title:

C-fms tyrosine kinase in complex with a quinolone inhibitor

Structure:

Cfms tyrosine kinase. Chain: a. Fragment: kinase domain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.80Å R-factor: 0.266 R-free: 0.296

Authors:

C.Schubert,C.Schalk-Hihi

Key ref:

C.Schubert et al. (2007). Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors. J Biol Chem, 282, 4094-4101. PubMed id: 17132624 DOI: 10.1074/jbc.M608183200

Date:

11-Aug-06 Release date: 28-Nov-06

Protein chain

P07333  (CSF1R_HUMAN) -  Macrophage colony-stimulating factor 1 receptor from Homo sapiens

Seq: 972 a.a.

Struc: 303 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor 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.M608183200

J Biol Chem 282:4094-4101 (2007)

PubMed id: 17132624

Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors.

C.Schubert, C.Schalk-Hihi, G.T.Struble, H.C.Ma, I.P.Petrounia, B.Brandt, I.C.Deckman, R.J.Patch, M.R.Player, J.C.Spurlino, B.A.Springer.

ABSTRACT

The cFMS proto-oncogene encodes for the colony-stimulating factor-1 receptor, a receptor-tyrosine kinase responsible for the differentiation and maturation of certain macrophages. Upon binding its ligand colony-stimulating factor-1 cFMS autophosphorylates, dimerizes, and induces phosphorylation of downstream targets. We report the novel crystal structure of unphosphorylated cFMS in complex with two members of different classes of drug-like protein kinase inhibitors. cFMS exhibits a typical bi-lobal kinase fold, and its activation loop and DFG motif are found to be in the canonical inactive conformation. Both ATP competitive inhibitors are bound in the active site and demonstrate a binding mode similar to that of STI-571 bound to cABL. The DFG motif is prevented from switching into the catalytically competent conformation through interactions with the inhibitors. Activation of cFMS is also inhibited by the juxtamembrane domain, which interacts with residues of the active site and prevents formation of the activated kinase. Together the structures of cFMS provide further insight into the autoinhibition of receptor-tyrosine kinases via their respective juxtamembrane domains; additionally the binding mode of two novel classes of kinase inhibitors will guide the design of novel molecules targeting macrophage-related diseases.

Selected figure(s)

Figure 1.
FIGURE 1. A, overview of the cFMS structure (TIE2-KID) with bound inhibitor 1. Structural elements are color-coded: blue, (N)ucleotide binding loop (P-loop); red, activation loop; green, catalytic loop; salmon, hinge region; cyan, KID; yellow, JM domain. B, structures of the inhibitors used in this study, 1 arylamide series inhibitor, 2 quinolone series inhibitor.

Figure 3.
FIGURE 3. Role of the JM domain in stabilizing the inactive form of cFMS. cFMS is shown in a white surface representation, the activation loop (red) and the JM domain (yellow) were excluded from the surface calculation and are represented as red and yellow schemes, respectively. Trp^550 is also represented as a surface. The activation loop of activated cKIT (PDB-ID 1PKG), superimposed onto cFMS, is shown in green. In its autoinhibited state, the JM domain of cFMS inserts itself into the active site and prevents the activation loop from switching into an active conformation.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 4094-4101) copyright 2007.

Figures were selected by the author.