3CLY

Crystal Structure of FGF Receptor 2 (FGFR2) Kinase Domains Trapped in Trans-Phosphorylation Reaction

Summary for 3CLY

• Entry DOI: 10.2210/pdb3cly/pdb
• Related: 2PSQ 2PVF
• Descriptor: Fibroblast growth factor receptor 2, MAGNESIUM ION, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (4 entities in total)
• Functional Keywords: kinase domain, trans-phosphorylation, atp-binding, disease mutation, ectodermal dysplasia, glycoprotein, heparin-binding, immunoglobulin domain, lacrimo-auriculo-dento-digital syndrome, membrane, nucleotide-binding, phosphoprotein, receptor, secreted, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 3: Cell membrane; Single-pass type I membrane protein. Isoform 14: Secreted. Isoform 19: Secreted: P21802
• Total number of polymer chains: 1
• Total formula weight: 39011.65

Authors

Chen, H.,Mohammadi, M. (deposition date: 2008-03-20, release date: 2009-02-03, Last modification date: 2024-10-30)

Primary citation

Chen, H.,Xu, C.F.,Ma, J.,Eliseenkova, A.V.,Li, W.,Pollock, P.M.,Pitteloud, N.,Miller, W.T.,Neubert, T.A.,Mohammadi, M.
A crystallographic snapshot of tyrosine trans-phosphorylation in action
Proc.Natl.Acad.Sci.USA, 105:19660-19665, 2008

PubMed Abstract: Tyrosine trans-phosphorylation is a key event in receptor tyrosine kinase signaling, yet, the structural basis for this process has eluded definition. Here, we present the crystal structure of the FGF receptor 2 kinases caught in the act of trans-phosphorylation of Y769, the major C-terminal phosphorylation site. The structure reveals that enzyme- and substrate-acting kinases engage each other through elaborate and specific interactions not only in the immediate vicinity of Y769 and the enzyme active site, but also in regions that are as much of 18 A away from D626, the catalytic base in the enzyme active site. These interactions lead to an unprecedented level of specificity and precision during the trans-phosphorylation on Y769. Time-resolved mass spectrometry analysis supports the observed mechanism of trans-phosphorylation. Our data provide a molecular framework for understanding the mechanism of action of Kallmann syndrome mutations and the order of trans-phosphorylation reactions in FGFRs. We propose that the salient mechanistic features of Y769 trans-phosphorylation are applicable to trans-phosphorylation of the equivalent major phosphorylation sites in many other RTKs.

PubMed: 19060208
DOI: 10.1073/pnas.0807752105

Experimental method

X-RAY DIFFRACTION (2 Å)