PDBsum entry 4pgz

Transferase

PDB id: 4pgz

Contents

Protein chains

165 a.a.

197 a.a.

Ligands

NAG ×3

Metals

_CO ×5

Waters ×82

PDB id:

4pgz

Name:

Transferase

Title:

Structural basis of kit activation by oncogenic mutations in the extracellular region reveals a zipper-like mechanism for ligand- dependent or oncogenic receptor tyrosine kinase activation

Structure:

Mast/stem cell growth factor receptor kit. Chain: c, a, b. Fragment: unp residues 308-514. Synonym: scfr,piebald trait protein,pbt,proto-oncogenE C-kit, tyrosine-protein kinase kit,p145 c-kit,v-kit hardy-zuckerman 4 feline sarcoma viral oncogene homolog. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kit, scfr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.40Å R-factor: 0.233 R-free: 0.262

Authors:

A.V.Reshetnyak,T.J.Boggon,I.Lax,J.Schlessinger

Key ref:

A.V.Reshetnyak et al. (2015). The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer. Mol Cell, 57, 191-201. PubMed id: 25544564 DOI: 10.1016/j.molcel.2014.11.021

Date:

03-May-14 Release date: 18-Mar-15

Protein chain

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

Seq: 976 a.a.

Struc: 165 a.a.*

Protein chains

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

Seq: 976 a.a.

Struc: 197 a.a.*

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

Enzyme reactions

• Enzyme class: Chains C, A, B: 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 = NAG) matches with 41.38% similarity) + ADP + H(+)

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

Added reference

DOI no: 10.1016/j.molcel.2014.11.021

Mol Cell 57:191-201 (2015)

PubMed id: 25544564

The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer.

A.V.Reshetnyak, Y.Opatowsky, T.J.Boggon, E.Folta-Stogniew, F.Tome, I.Lax, J.Schlessinger.

ABSTRACT

The receptor tyrosine kinase KIT plays an important role in development of germ cells, hematopoietic cells, and interstitial pacemaker cells. Oncogenic KIT mutations play an important "driver" role in gastrointestinal stromal tumors, acute myeloid leukemias, and melanoma, among other cancers. Here we describe the crystal structure of a recurring somatic oncogenic mutation located in the C-terminal Ig-like domain (D5) of the ectodomain, rendering KIT tyrosine kinase activity constitutively activated. The structural analysis, together with biochemical and biophysical experiments and detailed analyses of the activities of a variety of oncogenic KIT mutations, reveals that the strength of homotypic contacts and the cooperativity in the action of D4D5 regions determines whether KIT is normally regulated or constitutively activated in cancers. We propose that cooperative interactions mediated by multiple weak homotypic contacts between receptor molecules are responsible for regulating normal ligand-dependent or oncogenic RTK activation via a "zipper-like" mechanism for receptor activation.