PDBsum entry 4ckj

Transferase

PDB id: 4ckj

Contents

Protein chain

293 a.a.

Ligands

ADN

FMT ×16

Waters ×107

PDB id:

4ckj

Name:

Transferase

Title:

Crystal structure of ret tyrosine kinase domain bound to adenosine

Structure:

Proto-oncogene tyrosine-protein kinase receptor ret. Chain: a. Fragment: residues 705-1013. Synonym: cadherin family member 12, proto-oncogenE C-ret. Engineered: yes

Source:

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

Resolution:

1.65Å R-factor: 0.155 R-free: 0.181

Authors:

I.Plaza-Menacho,K.Barnouin,K.Goodman,R.J.Martinez-Torres,A.Borg, J.Murray-Rust,S.Mouilleron,P.Knowles,N.Q.Mcdonald

Key ref:

I.Plaza-Menacho et al. (2014). Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans. Mol Cell, 53, 738-751. PubMed id: 24560924 DOI: 10.1016/j.molcel.2014.01.015

Date:

06-Jan-14 Release date: 05-Mar-14

Protein chain

P07949  (RET_HUMAN) -  Proto-oncogene tyrosine-protein kinase receptor Ret from Homo sapiens

Seq: 1114 a.a.

Struc: 293 a.a.*

* PDB and UniProt seqs differ at 5 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⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = ADN) matches with 70.37% similarity) + ADP + H(+)

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

Added reference

DOI no: 10.1016/j.molcel.2014.01.015

Mol Cell 53:738-751 (2014)

PubMed id: 24560924

Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans.

I.Plaza-Menacho, K.Barnouin, K.Goodman, R.J.Martínez-Torres, A.Borg, J.Murray-Rust, S.Mouilleron, P.Knowles, N.Q.McDonald.

ABSTRACT

To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the kinase domain core, while sites within the activation loop only form at later time points. Comparison with oncogenic RET kinase revealed that late autophosphorylation sites become phosphorylated much earlier than wild-type RET, which is due to a combination of an enhanced enzymatic activity, increased ATP affinity, and surprisingly, by providing a better intermolecular substrate. Structural analysis of oncogenic M918T and wild-type RET kinase domains reveal a cis-inhibitory mechanism involving tethering contacts between the glycine-rich loop, activation loop, and αC-helix. Tether mutations only affected substrate presentation but perturbed the autophosphorylation trajectory similar to oncogenic mutations. This study reveals an unappreciated role for oncogenic RET kinase mutations in promoting intermolecular autophosphorylation by enhancing substrate presentation.