美国和德国科学家近日利用X射线结晶成像(X-ray crystallographic images)技术，揭示了心脏病生化反应过程中某个独特的分子调控路径。这一发现为将来心脏病的治疗提供了新的标靶。相关论文发表在12月21日的《科学》(Science)杂志上。
之前科学家已经知道，高血压及相关疾病患者体内会释放出血管紧缩素(angiotensin)等激素，这些激素能够附着在细胞表面受体，激活蛋白G-alpha-q，并能够控制信号传导路径中调控细胞生长和基因表达的蛋白RhoA的活性，从而引发心脏细胞的异常生长，某些情况下就会导致心脏病。然而，科学家一直没有弄清G-alpha-q和RhoA之间的信号传导路径。
在最新的研究中，美国密歇根大学的结构生物学家John Tesmer和研究小组利用高分辨率的X射线结晶成像技术，确定了一种在G-alpha-q和RhoA之间传递信号的酶——p63RhoGEF的原子结构。随后的动物实验证实了这三种分子间的相互作用，以及它们对于平滑肌功能的重要性。
Tesmer说：“我们捕获了这三种蛋白的图像，研究了它们的相互作用。从本质上来说，这是一个以前未被认识到的信号路径，人们可以利用它作为标靶来治疗心血管疾病。”(科学网梅进/编译)
原始出处:
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: tesmerjj@umich.edu (J.J.G.T.);
