PDBsum entry 2py3

Transferase

PDB id: 2py3

Contents

Protein chains

282 a.a. *

Ligands

SO4 ×4

ACP ×2

Metals

_MG ×4

Waters ×172

* Residue conservation analysis

PDB id:

2py3

Name:

Transferase

Title:

Crystal structure of fgf receptor 2 (fgfr2) kinase domain harboring the pathogenic e565g mutation responsible for pfeiffer syndrome

Structure:

Fibroblast growth factor receptor 2. Chain: a, b. Fragment: kinase domain. Synonym: fgfr-2, keratinocyte growth factor receptor 2, cd332 antigen. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr2, bek, ksam. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.30Å R-factor: 0.217 R-free: 0.252

Authors:

H.Chen,M.Mohammadi

Key ref:

H.Chen et al. (2007). A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Mol Cell, 27, 717-730. PubMed id: 17803937 DOI: 10.1016/j.molcel.2007.06.028

Date:

15-May-07 Release date: 25-Sep-07

Protein chains

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

Seq: 821 a.a.

Struc: 282 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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.molcel.2007.06.028

Mol Cell 27:717-730 (2007)

PubMed id: 17803937

A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases.

H.Chen, J.Ma, W.Li, A.V.Eliseenkova, C.Xu, T.A.Neubert, W.T.Miller, M.Mohammadi.

ABSTRACT

Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory "molecular brake" mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly.

Selected figure(s)

Figure 3.
Figure 3. The Molecular Brake at the Kinase Hinge Region of FGFR2K Regulates the Kinase Activation and Is Disengaged Either by A Loop Tyrosine Phosphorylation or Directly by the Pathogenic Mutations
(A) In the unphosphorylated wild-type structure, residues N549, E565, and K641 form a network of hydrogen bonds in the kinase hinge region, which serves as a molecular brake to keep the enzyme in an inactive state.
(B) The molecular brake is disengaged in the A loop tyrosine phosphorylated wild-type FGFR2K structure. This molecular brake is also disengaged in the unphosphorylated mutant FGFR2K structures (C–G). To assist the readers, the whole unphosphorylated wild-type FGFR2K structure is also shown in cartoon and solid semitransparent surface, and the kinase hinge region is boxed. Atom colorings are as follows: oxygens in red, nitrogens in blue, and carbons are colored according to the kinase region to which they belong. The kinase hinge, the αC-β4 loop (shown in sticks in [A]–[G]), and β8 strand are colored green, wheat, and cyan, respectively. The rest of the N lobe and C lobe is colored light purple and light blue, respectively. The three critical hydrogen bonds between N549 and the backbone atoms of αC-β4 loop are highlighted by red dashed lines. The remaining hydrogen bonds are shown as black dashed lines.

Figure 6.
Figure 6. The Autoinhibition by the Molecular Brake Is a Common Regulatory Mechanism for Many RTKs
(A)–(E) show the presence of the engaged molecular brake at the kinase hinge region of unphosphorylated wild-type FGFR1 (PDB ID: 1FGK), CSF1R (PDB ID: 2I1M), VEGFR2 (PDB ID: 1VR2), TEK (PDB ID: 1FVR), and c-KIT (PDB ID: 1T45) kinases, respectively. (F) shows the disengagement of the molecular brake at the kinase hinge region of an “active” c-KIT kinase (PDB ID: 1PKG). Coloring scheme is as in Figure 3.

The above figures are reprinted from an Open Access publication published by Cell Press: Mol Cell (2007, 27, 717-730) copyright 2007.

Figures were selected by an automated process.