神经营养因子-3与p75NTR胞外区复合物的晶体结构，蓝色部分为p75NTR胞外区(两个分子)， 红色与黄色为NT-3的两个单体。绿色为p75NTR上的糖基化位点。
2008年7月2日，《自然》（Nature）杂志在线发表了中国科学院生物物理所江涛课题组题为“Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex” 的研究论文。该论文报道了神经营养因子3与其受体p75NTR胞外区复合物的晶体结构，研究结果揭示了神经营养因子与其受体p75NTR相互作用的方式与结构基础。
神经营养因子是一类对神经元的发育、存活和凋亡起重要作用的蛋白质，其成员包括神经生长因子（NGF），脑源性生长因子(BDNF)，神经营养因子3(NT-3)，神经营养因子4(NT-4)等，这些蛋白质是治疗神经损伤等疾病的潜在药物标靶。过去的研究表明，神经营养因子有两种不同的膜蛋白受体，分别为p75NTR 受体和酪氨酸激酶受体Trk。神经营养因子通过与这两种受体的胞外区相互作用，将有关神经细胞存活和凋亡的信号传递到细胞内部，从而调控细胞的发育与凋亡。p75NTR可以与所有的神经营养因子相结合，但是p75NTR与神经营养因子的结合方式一直存在争议。此外，p75NTR与Trk之间既存在协同作用，又存在拮抗作用， 但是详细的协同调控机制仍有待进一步研究来阐明。
该论文工作利用X-射线晶体学方法解析了NT-3与p75NTR胞外区复合物的2.6埃分辨率的三维结构，并开展了相关的生化研究。研究结果揭示了神经营养因子-3与p75NTR的特异性结合方式，使人们得以更加深入地了解神经营养因子与受体相互作用的机制，同时也为以神经营养因子为标靶的药物开发提供了重要的结构基础。
这项工作由中科院生物物理所江涛研究组的龚勇博士和曹鹏博士等共同完成。该研究课题得到了科技部、国家自然科学基金委和中国科学院的资助。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature，doi:10.1038/nature07089，Yong Gong，Tao Jiang
Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex
Yong Gong1,2, Peng Cao1,2, Hong-jun Yu1 & Tao Jiang1
National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
These authors contributed equally to this work.
Correspondence to: Tao Jiang1 Correspondence and requests for materials should be addressed to T.J. (Email: tjiang@ibp.ac.cn).
Neurotrophins (NTs) are important regulators for the survival, differentiation and maintenance of different peripheral and central neurons. NTs bind to two distinct classes of glycosylated receptor: the p75 neurotrophin receptor (p75NTR) and tyrosine kinase receptors (Trks). Whereas p75NTR binds to all NTs, the Trk subtypes are specific for each NT1, 2. The question of whether NTs stimulate p75NTR by inducing receptor homodimerization is still under debate. Here we report the 2.6-Å resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75NTR. In contrast to the previously reported asymmetric complex structure, which contains a dimer of nerve growth factor (NGF) bound to a single ectodomain of deglycosylated p75NTR (ref. 3), we show that NT-3 forms a central homodimer around which two glycosylated p75NTR molecules bind symmetrically. Symmetrical binding occurs along the NT-3 interfaces, resulting in a 2:2 ligand–receptor cluster. A comparison of the symmetrical and asymmetric structures reveals significant differences in ligand–receptor interactions and p75NTR conformations. Biochemical experiments indicate that both NT-3 and NGF bind to p75NTR with 2:2 stoichiometry in solution, whereas the 2:1 complexes are the result of artificial deglycosylation. We therefore propose that the symmetrical 2:2 complex reflects a native state of p75NTR activation at the cell surface. These results provide a model for NTs-p75NTR recognition and signal generation, as well as insights into coordination between p75NTR and Trks.
