3OJV

Crystal Structure of FGF1 complexed with the ectodomain of FGFR1c exhibiting an ordered ligand specificity-determining betaC'-betaE loop

3OJV の概要

• エントリーDOI: 10.2210/pdb3ojv/pdb
• 関連するPDBエントリー: 1DJS 1EVT 1RY7 3OJ2 3OJM
• 分子名称: Heparin-binding growth factor 1, Basic fibroblast growth factor receptor 1, 4-deoxy-2-O-sulfo-alpha-L-threo-hex-4-enopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: beta trefoil motif, immunoglobulin-like domain, growth factor, growth factor receptor, extracellular, cytokine-signaling protein complex, cytokine/signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 83325.15

構造登録者

Beenken, A.,Mohammadi, M. (登録日: 2010-08-23, 公開日: 2011-12-28, 最終更新日: 2023-09-06)

主引用文献

Beenken, A.,Eliseenkova, A.V.,Ibrahimi, O.A.,Olsen, S.K.,Mohammadi, M.
Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1.
J.Biol.Chem., 287:3067-3078, 2012

PubMed Abstract: Tissue-specific alternative splicing in the second half of Ig-like domain 3 (D3) of fibroblast growth factor receptors 1-3 (FGFR1 to -3) generates epithelial FGFR1b-FGFR3b and mesenchymal FGFR1c-FGFR3c splice isoforms. This splicing event establishes a selectivity filter to restrict the ligand binding specificity of FGFRb and FGFRc isoforms to mesenchymally and epithelially derived fibroblast growth factors (FGFs), respectively. FGF1 is termed the "universal FGFR ligand" because it overrides this specificity barrier. To elucidate the molecular basis for FGF1 cross-reactivity with the "b" and "c" splice isoforms of FGFRs, we determined the first crystal structure of FGF1 in complex with an FGFRb isoform, FGFR2b, at 2.1 Å resolution. Comparison of the FGF1-FGFR2b structure with the three previously published FGF1-FGFRc structures reveals that plasticity in the interactions of the N-terminal region of FGF1 with FGFR D3 is the main determinant of FGF1 cross-reactivity with both isoforms of FGFRs. In support of our structural data, we demonstrate that substitution of three N-terminal residues (Gly-19, His-25, and Phe-26) of FGF2 (a ligand that does not bind FGFR2b) for the corresponding residues of FGF1 (Phe-16, Asn-22, and Tyr-23) enables the FGF2 triple mutant to bind and activate FGFR2b. These findings taken together with our previous structural data on receptor binding specificity of FGF2, FGF8, and FGF10 conclusively show that sequence divergence at the N termini of FGFs is the primary regulator of the receptor binding specificity and promiscuity of FGFs.

PubMed: 22057274
DOI: 10.1074/jbc.M111.275891

実験手法

X-RAY DIFFRACTION (2.6 Å)