title: Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.
abstract: The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 A resolution has been determined. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led us to propose a revised model for FGFR dimerization. Biochemical data in support of this model are also presented. This model provides a structural basis for FGFR activation by small molecule heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: J
authors.initials: J
authors.lastname: Schlessinger
authors.forename: A N
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: O A
authors.initials: OA
authors.lastname: Ibrahimi
authors.forename: A V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: B K
authors.initials: BK
authors.lastname: Yeh
authors.forename: A
authors.initials: A
authors.lastname: Yayon
authors.forename: R J
authors.initials: RJ
authors.lastname: Linhardt
authors.forename: M
authors.initials: M
authors.lastname: Mohammadi
mesh_terms: D001665:Binding Sites; D003461:Crystallography; D019281:Dimerization; D005346:Fibroblast Growth Factors / Q000737:chemistry* / Q000378:metabolism; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry* / Q000378:metabolism; D013431:Sulfates / Q000737:chemistry / Q000378:metabolism
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D013431:Sulfates; D005346:Fibroblast Growth Factors; D006493:Heparin