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.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Juha P
authors.initials: JP
authors.lastname: Himanen
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Goldgur
authors.forename: Hui
authors.initials: H
authors.lastname: Miao
authors.forename: Eugene
authors.initials: E
authors.lastname: Myshkin
authors.forename: Hong
authors.initials: H
authors.lastname: Guo
authors.forename: Matthias
authors.initials: M
authors.lastname: Buck
authors.forename: My
authors.initials: M
authors.lastname: Nguyen
authors.forename: Kanagalaghatta R
authors.initials: KR
authors.lastname: Rajashankar
authors.forename: Bingcheng
authors.initials: B
authors.lastname: Wang
authors.forename: Dimitar B
authors.initials: DB
authors.lastname: Nikolov
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D036382:Ephrin-A1 / Q000737:chemistry*; D036383:Ephrin-A2 / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D036081:Receptors, Eph Family / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D055672:Static Electricity
chemical_list: D036382:Ephrin-A1; D036383:Ephrin-A2; D008024:Ligands; D036081:Receptors, Eph Family