Structural and chemical biology of membrane proteins

我们的实验室研究了一些完整的膜蛋白家族的功能的结构基础。我们将联合收割机X射线晶体学与功能分析相结合，并采用一系列生物化学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）是一个大的，不同的一组完整的膜蛋白，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与不同部位结合来特异性地抑制特定K+通道亚型的离子传导，因此已经成为神经科学中不可缺少的工具。然而，在没有与K+通道的毒素复合物的共晶体结构的情况下，通过特定毒素识别特定K+通道的结构基础仍然不清楚。我的博士后工作导致了K+通道和蝎毒毒素之间的复合物的第一个晶体结构。目前，我们正在研究K+通道与其他毒素的结构，特别是从蛇毒中分离的Dendrotoxin。K+通道的不同部分被毒素靶向，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类型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，我们将注意力集中在将铁带入线粒体的线粒体内膜转运蛋白上。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中心组分，铁硫簇是参与广泛细胞活动的蛋白质所需的重要辅因子，即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，以获得足够的生物化学和生物物理特性的纯化材料。

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.