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

PDB id:

1pkg

Name:

Transferase activator

Title:

Structure of a c-kit kinase product complex

Structure:

C-kit protein. Chain: a, b. Fragment: catalytic domain. Engineered: yes

Source:

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

Resolution:

2.90Å R-factor: 0.229 R-free: 0.311

Authors:

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

Key ref:

C.D.Mol et al. (2003). Structure of a c-kit product complex reveals the basis for kinase transactivation. J Biol Chem, 278, 31461-31464. PubMed id: 12824176 DOI: 10.1074/jbc.C300186200

Date:

05-Jun-03 Release date: 12-Aug-03

Protein chains

P10721  (KIT_HUMAN) -  Mast/stem cell growth factor receptor Kit from Homo sapiens

Seq: 976 a.a.

Struc: 292 a.a.

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⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = ADP) corresponds exactly) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.C300186200

J Biol Chem 278:31461-31464 (2003)

PubMed id: 12824176

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

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.

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.

Selected figure(s)

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.

Figures were selected by an automated process.