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【文章导读】日前，清华大学和MRC分子生物学实验室的研究团队通过单颗粒低温电子显微技术，解析了兔RyR1与其调节子FKBP12结合时的结构，总体分辨率达到了3.8 ?。这一成果于12月15日发表在Nature杂志网站上。
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清华颜宁教授本月连发Nature、Science文章
来自清华大学的研究人员报道称，她们利用脂质立方相结晶法和微聚焦X射线衍射法，揭示出了葡萄糖转运蛋白识别及转运配体的分子基础。研究结果发布在7月15日的《自然》（Nature）杂志上。清华大学的颜宁（Nieng Yan）教授是这篇论文的通讯作者。2007年作为普林斯顿大学博士的颜宁受聘于清华大学医学院，成为清华最年轻的教授、博士生导师。在回国的几年间，颜宁教授研究组主要聚焦于膜蛋白、胆固醇代谢调控通路相关因子的结构生物学研究，在Science、Nature、Cell等杂志上发表多篇重要的论文，并荣获了中国青年女科学家奖、HHMI国际青年科学家奖等奖励。
葡萄糖代谢对于细胞新陈代谢、生长及维持稳态起着至关重要的作用，而葡萄糖的代谢取决于细胞对葡萄糖的摄取。然而，葡萄糖作为一种有机大分子无法自由通过细胞膜脂质双层结构进入细胞，细胞对葡萄糖的摄入需要借助细胞膜上的葡萄糖转运蛋白（glucose　transporters，简称GLUT）才能得以实现。人类的14种GLUTs各自呈现独特的时空分布，显示出不同的转运动力学、能力和底物选择性。
GLUT1～4是最明确确定特征的溶质转运蛋白。GLUT1是第一个被确定特征的转运蛋白，为认识溶质转运提供了一个范例。GLUT1广泛表达于多种组织细胞调节葡萄糖摄取，是负责红细胞的葡萄糖摄入以及穿越血脑屏障运输的主要葡萄糖转运蛋白；GLUT2在胰腺β细胞、肠、肾和肝中表达，可响应喂食或禁食状态来控制葡萄糖的摄取和外流。；GLUT3被称作为“神经元葡萄糖转运蛋白”，主要在神经元中发挥功能，它还负责精子、植入前胚胎和循环红血细胞的葡萄糖摄取。GLUT4可对脂肪细胞和肌肉中的胰岛素做出响应。
GLUTs失活性突变或异常调控与许多的疾病，包括GLUT1缺陷综合症、FanconiCBickel综合症、2型及阿尔茨海默式症有关联。GLUT1和GLUT3在多种不同的实体瘤中过表达。在缺氧情况下对于葡萄糖的需求显着增高以补偿ATP的生成，这种现象便被称作为Warburg效应。基于过表达GLUTs的癌症及潜在疗法，例如采用正电子发射断层扫描来监测2-deoxy-2-[18F]fluoroglucose的摄取，吸引了越来越多的关注。此外，还有一些研究将焦点放在了利用葡萄糖转运蛋白来提高膜通透性及组织特异性传送抗癌药物上。确定GLUTs尤其是与配体构成的复合物的结构对于设计和优化配体的先决条件。
在这篇Nature文章中研究人员利用脂质立方相结晶法和微聚焦X射线衍射法，确定了向胞外闭合（outward-occluded）构象下人类GLUT3与d-葡萄糖复合物的结构，分辨率达到了1.5 &A；。这一高分辨率的结构使得能够辨别出d-葡萄糖的α-和β-异头物。此外，她们还获得了分辨率分别为2.6&A；和2.4 &A；向胞外开放及向胞外闭合两种构象下的GLUT3与外表面抑制子麦芽糖复合物的结构。在所有三种结构中，配体主要是由羧端结构域极性残基协调。跨膜片段TM7胞外部分显着局部重排是从向胞外开放构象转变为向胞外闭合的必要条件。此外，研究人员还比较了面向外的GLUT3结构与向内开放GLUT1的结构。
这项研究为了解GLUTs的机制及动力学提供了一个重要的框架，并为有关合理设计和优化配体提供了一些重要的新见解。
此外，7月10日的《科学》（Science）杂志上还发布颜宁课题组的另一重大研究成果。清华大学的研究人员通过分析分枝杆菌Insig同系物的晶体结构，并结合一些生化实验揭示出了这些胆固醇感应蛋白监控胆固醇水平的分子机制。研究结果为进一步地了解Insig和SREBP信号通路的功能和机制提供了一个重要的框架（相关阅读：）。（）
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生物谷推荐的英文原文：
Molecular basis of ligand recognition and transport by glucose transporters
The major facilitator superfamily glucose transporters， exemplified by human GLUT1C4， have been central to the study of solute transport. Using lipidic cubic phase crystallization and microfocus X-ray diffraction， we determined the structure of human GLUT3 in complex with D-glucose at 1.5 &A resolution in an outward-occluded conformation. The high-resolution structure allows discrimination of both α- and β-anomers of D-glucose. Two additional structures of GLUT3 bound to the exofacial inhibitor maltose were obtained at 2.6 &A in the outward-open and 2.4 &A in the outward-occluded states. In all three structures， the ligands are predominantly coordinated by polar residues from the carboxy terminal domain. Conformational transition from outward-open to outward-occluded entails a prominent local rearrangement of the extracellular part of transmembrane segment TM7. Comparison of the outward-facing GLUT3 structures with the inward-open GLUT1 provides insights into the alternating access cycle for GLUTs， whereby the C-terminal domain provides the primary substrate-binding site and the amino-terminal domain undergoes rigid-body rotation with respect to the C-terminal domain. Our studies provide an important framework for the mechanistic and kinetic understanding of GLUTs and shed light on structure-guided ligand design.
关键词：颜宁,葡萄糖代谢,GLUT3
信息来源:生物通
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Scientific Discipline
Biochemistry, Structural Biology
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Institution
Tsinghua University
Current Position
Dr. Yan is a professor in the School of Medicine at Tsinghua University, Beijing, China.
Nieng Yan combines structural biology, biochemistry, and molecular biophysics to investigate the mechanisms of substrate recognition and transport, as well as electrochemical-?mechanical coupling of membrane transport proteins.Crystal structures of FucP and UraA...
Nieng Yan dreams of becoming a movie producer. Not a red-carpet, Hollywood star, but a creator of movies that reveal the intricate motion of molecules inside living cells. Yan finds beauty in the tiniest details of biology and wants to share that with others. She has already created static images of pumps on the cellular membrane that use energy to move molecules in and out of cells. Next, she wants to show the world the pumps’ movements. The pumps that Yan studies, and ones related to them, are mutated in a number of diseases and understanding their fluid motion could help design drugs to fix them.
As Yan began her undergraduate studies in biology at Tsinghua University in Beijing, science was emerging as a leading industry in China. Believing their daughter could make important contributions in this growing field, Yan’s parents urged her to pursue a career as either a doctor or a scientist.
“I wasn’t sure what I wanted to do myself until one summer as an undergraduate I worked in a structural biology lab,” she says. “As soon as I saw the beautiful crystals and the elegant structures of molecules, I was hooked.”
In that lab, Yan learned how to use X-ray crystallography to determine the arrangement of atoms within a molecule. The technique relies on the fact that when light shines through a crystal, it scatters in different patterns depending on the arrangement of molecules inside. Biological molecules can be turned into crystals by purifying them and letting the surrounding liquid slowly evaporate.
As a graduate student at Princeton University, Yan used X-ray crystallography to see the structure of a handful of proteins involved in cell death in the nematode Caenorhabditis elegans. Those structures revealed how one protein, EGL-1, binds to another, CED-9, to activate a linear pathway that eventually causes cells to self-destruct.
After Yan completed her Ph.D., her Princeton advisor, Yigong Shi, convinced her to stay on for a postdoctoral fellowship by presenting her with a new task—solving the structure of a protein embedded inside the plasma membrane of a cell. “For structural biologists, membrane proteins represent the most challenging targets,” Yan says. “I couldn’t turn down the challenge.”
Yan spent two years studying the structure, learning how to work with finicky membrane proteins. But before she could finish the project, she was offered a position at Tsinghua University in Beijing. At the age of 30, she became the youngest professor at her alma mater. She turned the research over to her Princeton labmates and returned to China.
Her work with membrane proteins was far from finished, however. Once settled in her new lab at Tsinghua, Yan set out to study the structures of transporters and channels—proteins that move molecules in and out of cells through the plasma membrane. That was in 2007. Yan has since found the crystal structures of three key transport proteins involved in moving nutrient molecules.
“These transport proteins are the customs officers for the cells,” she says. “They can very specifically select what they want to bring across in each direction.”
Working with an interdisciplinary team of scientists, Yan is attempting to figure out the structures of glucose transporters, information vital to the study of diabetes and some cancers. “Most cells rely on glucose as their major nutrient. The uptake of glucose is absolutely essential for life,” Yan says. Ultimately, she wants to create not just static images of the transporters but a series of images that illustrate changes that occur as transporters pump materials through the membrane.
“These transporters are very dynamic,” Yan notes. “It’d be great if we could capture many different structures of a transporter and make a continuous movie of how it moves through cycles.” Such a documentary, she adds, would offer a three-dimensional view of a protein’s structure, information that could help in the development of drugs designed to block or activate a particular protein.
Research Papers
AwardsYoung Scientist Award (North America Regional Winner), cosponsored by AAAS/Science and GE Healthcare您现在所在的位置： >
颜宁太牛了！刚发了Science，又一篇Nature
文章来源：生物通
作者：转发
发布时间： 12:00
　　导读：来自清华大学的研究人员报道称，她们利用脂质立方相结晶法和微聚焦X射线衍射法，揭示出了葡萄糖转运蛋白识别及转运配体的分子基础。研究结果发布在7月15日的《自然》（Nature）杂志上。
　　来自清华大学的研究人员报道称，她们利用脂质立方相结晶法和微聚焦X射线衍射法，揭示出了葡萄糖转运蛋白识别及转运配体的分子基础。研究结果发布在7月15日的《自然》（Nature）杂志上。
　　清华大学的颜宁（Nieng Yan）教授是这篇论文的通讯作者。2007年作为普林斯顿大学博士的颜宁受聘于清华大学医学院，成为清华最年轻的教授、博士生导师。在回国的几年间，颜宁教授研究组主要聚焦于膜蛋白、胆固醇代谢调控通路相关因子的结构生物学研究，在Science、Nature、Cell等杂志上发表多篇重要的论文，并荣获了中国青年女科学家奖、HHMI国际青年科学家奖等奖励。
　　葡萄糖代谢对于细胞新陈代谢、生长及维持稳态起着至关重要的作用，而葡萄糖的代谢取决于细胞对葡萄糖的摄取。然而，葡萄糖作为一种有机大分子无法自由通过细胞膜脂质双层结构进入细胞，细胞对葡萄糖的摄入需要借助细胞膜上的葡萄糖转运蛋白（glucose　transporters,简称GLUT）才能得以实现。人类的14种GLUTs各自呈现独特的时空分布，显示出不同的转运动力学、能力和底物选择性。
　　GLUT1～4是最明确确定特征的溶质转运蛋白。GLUT1是第一个被确定特征的转运蛋白，为认识溶质转运提供了一个范例。GLUT1广泛表达于多种组织细胞调节葡萄糖摄取，是负责红细胞的葡萄糖摄入以及穿越血脑屏障运输的主要葡萄糖转运蛋白；GLUT2在胰腺&细胞、肠、肾和肝中表达，可响应喂食或禁食状态来控制葡萄糖的摄取和外流。；GLUT3被称作为&神经元葡萄糖转运蛋白&，主要在神经元中发挥功能，它还负责精子、植入前胚胎和循环红血细胞的葡萄糖摄取。GLUT4可对脂肪细胞和肌肉中的胰岛素做出响应。
　　GLUTs失活性突变或异常调控与许多的疾病，包括GLUT1缺陷综合症、Fanconi&Bickel综合症、2型糖尿病及阿尔茨海默式症有关联。GLUT1和GLUT3在多种不同的实体瘤中过表达。在缺氧情况下肿瘤对于葡萄糖的需求显著增高以补偿ATP的生成，这种现象便被称作为Warburg效应。基于过表达GLUTs的癌症诊断及潜在疗法，例如采用正电子发射断层扫描来监测2-deoxy-2-[18F]fluoroglucose的摄取，吸引了越来越多的关注。此外，还有一些研究将焦点放在了利用葡萄糖转运蛋白来提高膜通透性及组织特异性传送抗癌药物上。确定GLUTs尤其是与配体构成的复合物的结构对于设计和优化配体的先决条件。
　　在这篇Nature文章中研究人员利用脂质立方相结晶法和微聚焦X射线衍射法，确定了向胞外闭合（outward-occluded）构象下人类GLUT3与d-葡萄糖复合物的结构，分辨率达到了1.5 &A。这一高分辨率的结构使得能够辨别出d-葡萄糖的&-和&-异头物。此外，她们还获得了分辨率分别为2.6 &A和2.4 &A向胞外开放及向胞外闭合两种构象下的GLUT3与外表面抑制子麦芽糖复合物的结构。在所有三种结构中，配体主要是由羧端结构域极性残基协调。跨膜片段TM7胞外部分显著局部重排是从向胞外开放构象转变为向胞外闭合的必要条件。此外，研究人员还比较了面向外的GLUT3结构与向内开放GLUT1的结构。
　　这项研究为了解GLUTs的机制及动力学提供了一个重要的框架，并为有关合理设计和优化配体提供了一些重要的新见解。
　　此外，7月10日的《科学》（Science）杂志上还发布颜宁课题组的另一重大研究成果。清华大学的研究人员通过分析分枝杆菌Insig同系物的晶体结构，并结合一些生化实验揭示出了这些胆固醇感应蛋白监控胆固醇水平的分子机制。研究结果为进一步地了解Insig和SREBP信号通路的功能和机制提供了一个重要的框架。