PDBsum entry 1pkg

Transferase activator

PDB id: 1pkg

Contents

Protein chains

292 a.a. *

Ligands

ADP ×2

Metals

_MG ×2

Waters ×3

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structure of a c-Kit product complex reveals the basis for kinase transactivation.

Authors

C.D.Mol, K.B.Lim, V.Sridhar, H.Zou, E.Y.Chien, B.C.Sang, J.Nowakowski, D.B.Kassel, C.N.Cronin, D.E.Mcree.

Ref.

J Biol Chem, 2003, 278, 31461-31464. [DOI no: 10.1074/jbc.C300186200]

PubMed id

12824176

Abstract

The c-Kit proto-oncogene is a receptor protein-tyrosine kinase associated with several highly malignant human cancers. Upon binding its ligand, stem cell factor (SCF), c-Kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. Disease-causing human mutations that activate SCF-independent constitutive expression of c-Kit are found in acute myelogenous leukemia, human mast cell disease, and gastrointestinal stromal tumors. We report on the phosphorylation state and crystal structure of a c-Kit product complex. The c-Kit structure is in a fully active form, with ordered kinase activation and phosphate-binding loops. These results provide key insights into the molecular basis for c-Kit kinase transactivation to assist in the design of new competitive inhibitors targeting activated mutant forms of c-Kit that are resistant to current chemotherapy regimes.

Figure 3.
FIG. 3. Structure of active c-Kit kinase. The C ribbon illustrates the two-domain kinase fold and key structural elements, including the C-helix, phosphate-binding P-loop, adenine-recognition hinge loop, and kinase activation A-loop. The positions of the ADP, metal ion, and substrate peptide are also shown.

Figure 4.
FIG. 4. The c-Kit active site. Interactions at the c-Kit active site with Mg2^+, ADP, and phosphotyrosine are shown.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 31461-31464) copyright 2003.