Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex Journal Article
| Authors: | Himanen, J. P.; Goldgur, Y.; Miao, H.; Myshkin, E.; Guo, H.; Buck, M.; Nguyen, M.; Rajashankar, K. R.; Wang, B.; Nikolov, D. B. |
| Article Title: | Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex |
| Abstract: | Ephrin (Eph) receptor tyrosine kinases fall into two subclasses (A and B) according to preferences for their ephrin ligands. All published structural studies of Eph receptor/ephrin complexes involve B-class receptors. Here, we present the crystal structures of an A-class complex between EphA2 and ephrin-A1 and of unbound EphA2. Although these structures are similar overall to their B-class counterparts, they reveal important differences that define subclass specificity. The structures suggest that the A-class Eph receptor/ephrin interactions involve smaller rearrangements in the interacting partners, better described by a 'lock-and-key'-type binding mechanism, in contrast to the 'induced fit' mechanism defining the B-class molecules. This model is supported by structure-based mutagenesis and by differential requirements for ligand oligomerization by the two subclasses in cell-based Eph receptor activation assays. Finally, the structure of the unligated receptor reveals a homodimer assembly that might represent EphA2-specific homotypic cell adhesion interactions. |
| Keywords: | controlled study; human cell; binding affinity; protein function; protein protein interaction; cell line; protein binding; enzyme activation; drug design; amino acid sequence; molecular sequence data; protein multimerization; sequence alignment; molecular recognition; ligands; crystal structure; models, molecular; crystallography, x-ray; protein structure, tertiary; ephrin receptor a2; protein structure; enzyme specificity; cell interaction; static electricity; cell adhesion; ligand binding; protein structure, secondary; mutagenesis; benzoic acid derivative; ephrin receptor a1; drug protein binding; enzyme assay; oligomerization; ephrin-a1; ephrin-a2; receptors, eph family |
| Journal Title: | EMBO Reports |
| Volume: | 10 |
| Issue: | 7 |
| ISSN: | 1469-221X |
| Publisher: | Wiley Blackwell |
| Date Published: | 2009-07-01 |
| Start Page: | 722 |
| End Page: | 728 |
| Language: | English |
| DOI: | 10.1038/embor.2009.91 |
| PUBMED: | 19525919 |
| PROVIDER: | scopus |
| PMCID: | PMC2727437 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 30 November 2010" - "CODEN: ERMEA" - "Source: Scopus" |
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