3FY2

Human EphA3 Kinase and Juxtamembrane Region Bound to Substrate KQWDNYEFIW

Summary for 3FY2

• Entry DOI: 10.2210/pdb3fy2/pdb
• Related: 1IR3 2GSF 2QOC 3FXX
• Descriptor: Ephrin type-A receptor 3, peptide substrate (3 entities in total)
• Functional Keywords: receptor tyrosine kinase, juxtamembrane segment, structural genomics, peptide co-crystal structure, structural genomics consortium, sgc, atp-binding, cell membrane, glycoprotein, kinase, membrane, nucleotide-binding, phosphoprotein, receptor, secreted, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform 1: Cell membrane ; Single-pass type I membrane protein . Isoform 2: Secreted : P29320
• Total number of polymer chains: 2
• Total formula weight: 43249.28

Authors

Davis, T.,Walker, J.R.,Mackenzie, F.,Bountra, C.,Weigelt, J.,Arrowsmith, C.H.,Edwards, A.M.,Bochkarev, A.,Dhe-Paganon, S.,Structural Genomics Consortium (SGC) (deposition date: 2009-01-21, release date: 2009-02-03, Last modification date: 2023-09-06)

Primary citation

Davis, T.L.,Walker, J.R.,Allali-Hassani, A.,Parker, S.A.,Turk, B.E.,Dhe-Paganon, S.
Structural recognition of an optimized substrate for the ephrin family of receptor tyrosine kinases.
Febs J., 276:4395-4404, 2009

PubMed Abstract: Ephrin receptor tyrosine kinase A3 (EphA3, EC 2.7.10.1) is a member of a unique branch of the kinome in which downstream signaling occurs in both ligand- and receptor-expressing cells. Consequently, the ephrins and ephrin receptor tyrosine kinases often mediate processes involving cell-cell contact, including cellular adhesion or repulsion, developmental remodeling and neuronal mapping. The receptor is also frequently overexpressed in invasive cancers, including breast, small-cell lung and gastrointestinal cancers. However, little is known about direct substrates of EphA3 kinase and no chemical probes are available. Using a library approach, we found a short peptide sequence that is a good substrate for EphA3 and is suitable for co-crystallization studies. Complex structures show multiple contacts between kinase and substrates; in particular, two residues undergo conformational changes and by mutation are found to be important for substrate binding and turnover. In addition, a difference in catalytic efficiency between EPH kinase family members is observed. These results provide insight into the mechanism of substrate binding to these developmentally integral enzymes.

PubMed: 19678838
DOI: 10.1111/j.1742-4658.2009.07147.x

Experimental method

X-RAY DIFFRACTION (1.8 Å)