据physorg网站2006年9月13日报道,活细胞中各种各样的蛋白质担负着细胞大部分的工作。基因中的脱氧核糖核酸(DNA)序列发布制造这些蛋白质的指令。各种活体生物细胞中的核糖体和微型蛋白质加工厂分别负责从事读取基因指令和合成特定蛋白质的关键性工作。
哈利.洛勒尔是加州大学圣塔克鲁斯分校的一名分子生物学教授。他从事核糖体研究已经30多年。他研究的主要目标就是解开核糖体是如何工作和发展的。许多最为有效的抗生素的对象就是细菌核糖体。洛勒尔和其它科学家取得的研究成果推动了新型抗生素的开发,这些抗生素可以杀死那些对目前使用药物产生抗体的细菌。比如抗药性葡萄球菌感染就医院所面临的一个极为严重的问题。
洛勒尔实验室在1999年至2001年间取得突破,他们制作出了首个完整分子结构的高清晰图。现在,他所领导的研究小组已经制作出了更为高清晰的分子结构图,这使他们具备制作核糖体原子模型的能力。
新分子结构图为我们展示了以前从未见过的详细细节,并为我们展现出蛋白质合成过程中参与合成的确切核糖体部分。一篇专门论述此项研究发现的论文将刊登在9月22日的《细胞》杂志中,现在你可以在线查看该论文。
洛勒尔说,“现在我们能对过去几十年生物化学和遗传研究的许多结论进行解答。我们制作出的分子结构图将使我们全面了解核糖体的整个活动过程”。核糖体是由蛋白质和核糖核酸分子组成的复杂分子机器。洛勒尔实验室研究的细菌(嗜热栖热菌)核糖体由三个不同核糖核酸分子和50个不同蛋白质组成。
洛勒尔在二十世纪七十年代初期就提出核糖体中的核糖核酸成分担负着核糖体的关键功能。在当时,洛勒尔的这种想法被认为是“疯子观点”,但是洛勒尔和其它科学家的后续研究却证明他的观点是正确的。
加州大学圣塔克鲁斯分校核糖核酸分子生物学中心主任洛勒尔说,“当我们首次提出此项观点的时候,很多人认为我们的观点极其异端的。但是现在大家已经接受这种观点。我们最近的研究确认核糖体中的核糖核酸在核糖体的功能发挥方面起着关键性作用。蛋白质也起着很重要的作用,但是比起核糖核酸来却要逊色一些”。
为了制造一个新的蛋白质,基因中的脱氧核糖核酸序列会首先将一个遗传指令复制成一个核糖核酸分子信息。此时核糖体从核糖核酸信息中读取遗传代码,而后将该代码植入蛋白质结构当中。
蛋白质是一种通过折叠成复杂三维形状来执行其功能的线性分子。他们由氨基酸建筑块组成。氨基酸的排列顺序决定蛋白质的结构。氨基酸经核糖核酸分子转输进入核糖体中。在核糖体中,核糖核酸传输时通过核糖核酸信息认证特定序列的遗传代码,而后氨基酸以正确的序列加入其中。
洛勒尔研究小组制作的分子结构图不仅展示了核糖体的完整结构,而且还展示了核糖核酸信息及两个核糖核酸传输的整个范围。洛勒尔说,“我们现在掌握了核糖体、核糖核酸信息和核糖核酸传输之间相互作用的大部分情况”。
此项研究成果使我们对分子活动机理有了一个粗细的了解。洛勒尔将他制作的分子结构图与其它科研小组的分子结构图进行了比较,他发现核糖体或者核糖体的下层结构位置不同。目前他正在探索分子活动中核糖体活动的线索。他说,“我们下一步目标就是跟踪核糖体的其它功能,以制作出更为详细的核糖体分子结构图”。
此篇论文的作者除了洛勒尔外,还包括博士后研究员安德烈.库洛斯德勒维、资深科学家色尔格.特拉克哈洛维和博士后研究员马丁.劳尔博格。研究人员使用了一种名为X射线结晶学的技术,该技术能制造出净化核糖体晶体,而后使用聚集X射线光束透视这些晶体,并对产生的不同衍射模式进行分析。洛勒尔说,特拉克哈洛维负责准备这些晶体,库洛斯德勒维和劳尔博则负责利用结晶学对晶体进行实验,并找出核糖体的结构。
英文原文:
Biologists probe the machinery of cellular protein factories
Harry Noller, the Sinsheimer Professor of Molecular Biology at the University of California, Santa Cruz, has been studying the ribosome for more than 30 years. His main goal is to understand how the ribosome works and how it evolved, but there are also practical reasons to pursue this research. Many of the most effective antibiotics work by targeting bacterial ribosomes, and findings by Noller and others have led to the development of novel antibiotics that hold promise for use against germs that have developed resistance to current drugs. Drug-resistant staph infections, for example, are a serious problem in hospitals.
Noller's laboratory achieved breakthroughs in 1999 and 2001, producing the first high-resolution images of the molecular structure of a complete ribosome. Now, his team has made another major advance with an even higher-resolution image that enables them to construct an atom-by-atom model of the ribosome.
The new picture shows details never seen before and suggests how certain parts of the ribosome move during protein synthesis. A paper describing the new findings will be published in the September 22 issue of the journal Cell and is currently available online.
"We can now explain a lot of the results from biochemical and genetic studies carried out over the past several decades," Noller said. "This structure gives us another frame in the movie that will eventually show us the whole process of the ribosome in action."
The ribosome is a complex molecular machine made up of proteins and RNA molecules. The bacterial ribosomes studied in Noller's lab (obtained from the bacterium Thermus thermophilus) are made up of three different RNA molecules and more than 50 different proteins.
Noller proposed in the early 1970s that the RNA component was responsible for carrying out the ribosome's key functions. At the time it was considered a "crackpot idea," but subsequent findings by Noller and others proved he was right.
"It was a completely heterodox view when we first proposed it, but it is now the accepted paradigm," said Noller, who directs the Center for Molecular Biology of RNA at UCSC. "Our latest results confirm that the ribosomal RNA is really the key to ribosome function. The proteins are also involved, but more peripherally," he said.
To make a new protein, the genetic instructions are first copied from the DNA sequence of the gene into a messenger RNA molecule. The ribosome then reads the genetic code from the messenger RNA and translates it into the structure of a protein.
Proteins are linear molecules that fold into complex three-dimensional shapes to carry out their functions. They are made from amino acid building blocks, and the sequence of amino acids determines the protein's structure. Amino acids are carried to the ribosome by transfer RNA molecules. On the ribosome, the transfer RNAs recognize specific sequences of genetic code on the messenger RNA, and the amino acids are then joined together in the proper order.
The images from Noller's group not only show the complete ribosome, they show it with a messenger RNA and two full-length transfer RNAs bound to it. "We can now see the details of most of the interactions between the ribosome, the messenger RNA, and the transfer RNAs," Noller said.
The results provide a snapshot of the molecular machine in action. By comparing his images with those obtained by other groups that have caught the ribosome or its subunits in different positions, Noller is finding clues to the molecular motions with which the ribosome does its work.
"Our next goal is to trap the ribosome in other functional states to get more frames of the movie," he said.
The authors of the paper, in addition to Noller, are postdoctoral researcher Andrei Korostelev, senior scientist Sergei Trakhanov, and postdoctoral researcher Martin Laurberg. The researchers used a technique called x-ray crystallography, which involves growing crystals of purified ribosomes, shining a focused beam of x-rays through the crystals, and analyzing the resulting diffraction pattern. Trakhanov prepared the crystals and Korostelev and Laurberg performed the crystallography and solved the structure, Noller said.