PDBsum entry 2i0y

Transferase

PDB id: 2i0y

Contents

Protein chain

289 a.a.

Ligands

5CN

Waters ×101

References listed in PDB file

Key reference

Title

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

Authors

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.

Ref.

J Biol Chem, 2007, 282, 4094-4101. [DOI no: 10.1074/jbc.M608183200]

PubMed id

17132624

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.

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.