神經(jīng)營養(yǎng)因子-3與p75NTR胞外區(qū)復(fù)合物的晶體結(jié)構(gòu)，藍(lán)色部分為p75NTR胞外區(qū)(兩個(gè)分子),， 紅色與黃色為NT-3的兩個(gè)單體,。綠色為p75NTR上的糖基化位點(diǎn)。
2008年7月2日,，《自然》（Nature）雜志在線發(fā)表了中國科學(xué)院生物物理所江濤課題組題為“Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex” 的研究論文,。該論文報(bào)道了神經(jīng)營養(yǎng)因子3與其受體p75NTR胞外區(qū)復(fù)合物的晶體結(jié)構(gòu)，研究結(jié)果揭示了神經(jīng)營養(yǎng)因子與其受體p75NTR相互作用的方式與結(jié)構(gòu)基礎(chǔ),。
神經(jīng)營養(yǎng)因子是一類對(duì)神經(jīng)元的發(fā)育,、存活和凋亡起重要作用的蛋白質(zhì)，其成員包括神經(jīng)生長因子（NGF）,，腦源性生長因子(BDNF)，神經(jīng)營養(yǎng)因子3(NT-3),，神經(jīng)營養(yǎng)因子4(NT-4)等,，這些蛋白質(zhì)是治療神經(jīng)損傷等疾病的潛在藥物標(biāo)靶。過去的研究表明,，神經(jīng)營養(yǎng)因子有兩種不同的膜蛋白受體，分別為p75NTR 受體和酪氨酸激酶受體Trk,。神經(jīng)營養(yǎng)因子通過與這兩種受體的胞外區(qū)相互作用,，將有關(guān)神經(jīng)細(xì)胞存活和凋亡的信號(hào)傳遞到細(xì)胞內(nèi)部，從而調(diào)控細(xì)胞的發(fā)育與凋亡,。p75NTR可以與所有的神經(jīng)營養(yǎng)因子相結(jié)合,，但是p75NTR與神經(jīng)營養(yǎng)因子的結(jié)合方式一直存在爭議,。此外，p75NTR與Trk之間既存在協(xié)同作用,，又存在拮抗作用， 但是詳細(xì)的協(xié)同調(diào)控機(jī)制仍有待進(jìn)一步研究來闡明,。
該論文工作利用X-射線晶體學(xué)方法解析了NT-3與p75NTR胞外區(qū)復(fù)合物的2.6埃分辨率的三維結(jié)構(gòu),，并開展了相關(guān)的生化研究。研究結(jié)果揭示了神經(jīng)營養(yǎng)因子-3與p75NTR的特異性結(jié)合方式,，使人們得以更加深入地了解神經(jīng)營養(yǎng)因子與受體相互作用的機(jī)制，同時(shí)也為以神經(jīng)營養(yǎng)因子為標(biāo)靶的藥物開發(fā)提供了重要的結(jié)構(gòu)基礎(chǔ),。
這項(xiàng)工作由中科院生物物理所江濤研究組的龔勇博士和曹鵬博士等共同完成,。該研究課題得到了科技部、國家自然科學(xué)基金委和中國科學(xué)院的資助,。（生物谷Bioon.com）
生物谷推薦原始出處：
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: [email protected]).
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.
