Structural and chemical biology of membrane proteins

我们的实验室研究了一些完整膜蛋白家族功能的结构基础。我们将x射线晶体学与功能分析结合起来，采用一系列生化和生物物理技术来解决这些问题。1)钾离子选择性通道（K+通道）是一个庞大而多样的整体膜蛋白群，对正常的细胞功能至关重要。来自动物毒液的毒素能够通过结合不同部位特异性地抑制特定K+通道亚型的离子传导，因此成为神经科学中不可或缺的工具。然而，由于缺乏含有K+通道的毒素复合物的co&#8208；晶体结构，特定毒素识别特定K+通道的结构基础仍然不清楚。我的博士后工作导致了K+通道和蝎子毒液毒素之间复合物的第一个晶体结构。目前，我们正在与其他毒素，特别是从蛇毒中分离出来的树突毒素一起研究K+通道的结构。K+通道的不同部分是毒素的目标，因此每种不同类型的毒素通道复合物的结构将导致对这些非常重要的离子通道的独特方面及其在细胞生理学中的作用的见解。2)在第二个项目中，我们将重点关注将铁带入线粒体的线粒体内膜转运蛋白。随后，铁被用于血红素的生物合成，血红素是血红蛋白、肌红蛋白和细胞色素中血红素的核心成分，铁-硫簇是参与广泛细胞活动的蛋白质所需的重要辅助因子，如呼吸链复合物中的电子传递、调节传感、光合作用和DNA修复。我们目前正在使用异源表达获得足够的纯化材料进行生化和生物物理表征。

Our laboratory investigates the structural bases of functions of a number of integral membrane protein families. We combine x-ray crystallography together with functional analyses with a range of biochemical and biophysical techniques to approach these problems. 1) Potassium‐selective channels (K+ channels) are a large, diverse group of integral membrane proteins, crucial for proper cellular functioning. Toxins from animal venoms are able to specifically inhibit ion‐conduction by specific K+ channel subtypes by binding to different parts, and have thus emerged as indispensible tools in neuroscience. However, in the absence of a co‐crystal structure of a toxin‐complex with a K+ channel, the structural bases for recognition of specific K+ channels by specific toxins remain obscure. My postdoctoral work resulted in the first crystal structure of a complex between a K+ channel and a toxin from scorpion venom. Currently we are pursuing the structures of K+ channels with other toxins, specifically, Dendrotoxin, isolated from snake venom. Different parts of K+ channels are targeted by toxins, and thus structure of each distinct class of toxin-channel complexes will lead to insights about unique aspects of these very important class of ion channels and their role in cellular physiology. 2) In a second project, we are focusing our attention on mitochondrial inner membrane transporters that bring iron into mitochondria. Subsequently, the iron is utilized in the biosynthesis of heme, a central component of the heme in hemoglobin, myoglobin, and cytochromes , and iron-sulfur clusters, important cofactors required for proteins involved in a wide range of cellular activities, viz. electron transport in respiratory chain complexes, regulatory sensing, photosynthesis and DNA repair. We are currently using heterologous expression to obtain enough purified material for biochemical and biophysical characterization.