PDBsum entry 4j96

Transferase

PDB id: 4j96

Contents

Protein chains

302 a.a.

Ligands

SO4 ×3

FLC ×2

ACP

Metals

_MG

Waters ×183

PDB id:

4j96

Name:

Transferase

Title:

Crystal structure of fgf receptor 2 (fgfr2) kinase domain harboring the pathogenic gain-of-function k659m mutation identified in cervical cancer.

Structure:

Fibroblast growth factor receptor 2. Chain: a, b. Fragment: human fgf receptor 2 kinase domain (unp residues 458-768). Synonym: fgfr-2, k-sam, kgfr, keratinocyte growth factor receptor. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bek, fgfr2, kgfr, ksam. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.30Å R-factor: 0.178 R-free: 0.219

Authors:

H.Chen,M.Mohammadi

Key ref:

H.Chen et al. (2013). Cracking the molecular origin of intrinsic tyrosine kinase activity through analysis of pathogenic gain-of-function mutations. Cell Rep, 4, 376-384. PubMed id: 23871672 DOI: 10.1016/j.celrep.2013.06.025

Date:

15-Feb-13 Release date: 07-Aug-13

Protein chains

P21802  (FGFR2_HUMAN) -  Fibroblast growth factor receptor 2 from Homo sapiens

Seq: 821 a.a.

Struc: 302 a.a.*

* PDB and UniProt seqs differ at 2 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 = ACP) matches with 81.25% similarity) + ADP + H(+)

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

Added reference

DOI no: 10.1016/j.celrep.2013.06.025

Cell Rep 4:376-384 (2013)

PubMed id: 23871672

Cracking the molecular origin of intrinsic tyrosine kinase activity through analysis of pathogenic gain-of-function mutations.

H.Chen, Z.Huang, K.Dutta, S.Blais, T.A.Neubert, X.Li, D.Cowburn, N.J.Traaseth, M.Mohammadi.

ABSTRACT

The basal (ligand-independent) kinase activity of receptor tyrosine kinases (RTKs) promotes trans-phosphorylation on activation loop tyrosines upon ligand-induced receptor dimerization, thus upregulating intrinsic kinase activity and triggering intracellular signaling. To understand the molecular determinants of intrinsic kinase activity, we used X-ray crystallography and NMR spectroscopy to analyze pathogenic FGF receptor mutants with gradations in gain-of-function activity. These structural analyses revealed a "two-state" dynamic equilibrium model whereby the kinase toggles between an "inhibited," structurally rigid ground state and a more dynamic and heterogeneous active state. The pathogenic mutations have different abilities to shift this equilibrium toward the active state. The increase in the fractional population of FGF receptors in the active state correlates with the degree of gain-of-function activity and clinical severity. Our data demonstrate that the fractional population of RTKs in the active state determines intrinsic kinase activity and underscore how a slight increase in the active population of kinases can have grave consequences for human health.