美國和德國科學(xué)家近日利用X射線結(jié)晶成像(X-ray  crystallographic  images)技術(shù)，揭示了心臟病生化反應(yīng)過程中某個獨特的分子調(diào)控路徑,。這一發(fā)現(xiàn)為將來心臟病的治療提供了新的標(biāo)靶。相關(guān)論文發(fā)表在12月21日的《科學(xué)》(Science)雜志上,。        

之前科學(xué)家已經(jīng)知道,，高血壓及相關(guān)疾病患者體內(nèi)會釋放出血管緊縮素(angiotensin)等激素，這些激素能夠附著在細(xì)胞表面受體,，激活蛋白G-alpha-q,，并能夠控制信號傳導(dǎo)路徑中調(diào)控細(xì)胞生長和基因表達(dá)的蛋白RhoA的活性，從而引發(fā)心臟細(xì)胞的異常生長,，某些情況下就會導(dǎo)致心臟病,。然而，科學(xué)家一直沒有弄清G-alpha-q和RhoA之間的信號傳導(dǎo)路徑,。  

在最新的研究中,，美國密歇根大學(xué)的結(jié)構(gòu)生物學(xué)家John  Tesmer和研究小組利用高分辨率的X射線結(jié)晶成像技術(shù)，確定了一種在G-alpha-q和RhoA之間傳遞信號的酶——p63RhoGEF的原子結(jié)構(gòu),。隨后的動物實驗證實了這三種分子間的相互作用,，以及它們對于平滑肌功能的重要性。        

Tesmer說：“我們捕獲了這三種蛋白的圖像,，研究了它們的相互作用,。從本質(zhì)上來說，這是一個以前未被認(rèn)識到的信號路徑,，人們可以利用它作為標(biāo)靶來治療心血管疾病,。”(科學(xué)網(wǎng)梅進(jìn)/編譯)

原始出處:

Science 21 December 2007:
Vol. 318. no. 5858, pp. 1923 - 1927
DOI: 10.1126/science.1147554

Structure of Gq-p63RhoGEF-RhoA Complex Reveals a Pathway for the Activation of RhoA by GPCRs

Susanne Lutz,1* Aruna Shankaranarayanan,2,3* Cassandra Coco,2 Marc Ridilla,2 Mark R. Nance,2 Christiane Vettel,1 Doris Baltus,1 Chris R. Evelyn,4 Richard R. Neubig,4 Thomas Wieland,1 John J. G. Tesmer2,4

The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric guanine nucleotide–binding protein (G protein) Gq and thereby links Gq-coupled receptors (GPCRs) to the activation of the small-molecular-weight G protein RhoA. We determined the crystal structure of the Gq-p63RhoGEF-RhoA complex, detailing the interactions of Gq with the Dbl and pleckstrin homology (DH and PH) domains of p63RhoGEF. These interactions involve the effector-binding site and the C-terminal region of Gq and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of Gq effectors that appear to activate RhoA both in vitro and in intact cells. We propose that this structure represents the crux of an ancient signal transduction pathway that is expected to be important in an array of physiological processes.

1 Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Maybachstrasse 14, D-68169 Mannheim, Germany.
2 Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109–2216, USA.
3 Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712–0165, USA.
4 Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109–0632, USA.

* These authors contributed equally to this work.

 Present address: Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, IN 47907, USA.

 To whom correspondence should be addressed. E-mail: [email protected] (J.J.G.T.);