Harmer Nicholas J, Pellegrini Luca, Chirgadze Dima, Fernandez-Recio Juan, Blundell Tom L
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
Biochemistry. 2004 Jan 27;43(3):629-40. doi: 10.1021/bi035320k.
The 22 members of the FGF family have been implicated in cell proliferation, differentiation, survival, and migration. They are required for both development and maintenance of vertebrates, demonstrating an exquisite pattern of affinities for both protein and proteoglycan receptors. FGF19, one of the most divergent human FGFs, is unique in binding solely to one receptor, FGFR4. We have used molecular replacement to solve the crystal structure of FGF19 at 1.3 A resolution using five superimposed FGF structures as the search model. The structure shows that two novel disulfide bonds found in FGF19, one of which appears to be conserved among several of the other FGFs, stabilize extended loops. The key heparin-binding loops of FGF19 have radically different conformations and charge patterns, compared to other FGFs, correlating with the unusually low affinity of FGF19 for heparin. A model for the complex of FGF19 with FGFR4 demonstrates that unique sequences in both FGF19 and FGFR4 are key to the formation of the complex. The structure therefore offers a clear explanation for the unusual affinity of FGF19 for FGFR4 alone.
成纤维细胞生长因子（FGF）家族的22个成员与细胞增殖、分化、存活及迁移有关。它们对于脊椎动物的发育和维持都是必需的，对蛋白质和蛋白聚糖受体均表现出一种精妙的亲和模式。FGF19是人类FGF中差异最大的成员之一，其独特之处在于仅与一种受体FGFR4结合。我们利用分子置换法，以五个叠加的FGF结构作为搜索模型，解析出了分辨率为1.3埃的FGF19晶体结构。该结构显示，在FGF19中发现的两个新二硫键稳定了延伸环，其中一个二硫键在其他几种FGF中似乎是保守的。与其他FGF相比，FGF19的关键肝素结合环具有截然不同的构象和电荷模式，这与FGF19对肝素异常低的亲和力相关。FGF19与FGFR4复合物的模型表明，FGF19和FGFR4中的独特序列都是形成该复合物的关键。因此，该结构为FGF19仅对FGFR4具有异常亲和力提供了清晰的解释。
