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Protein Researchers Win Nobel Prize In Chemistry
nucal writes "The
2003 Nobel Prize in Chemistry was awarded to
Rod MacKinnon and
Peter Agree for their work on proteins that form ion and water channels in cell membranes. In particular, solving the structure of potassium channels was a major achievement, since this was the first multispan transmembrane protein structure to be solved by X-ray crystallography. There is also structural information on aquaporins (water channels) as well."
There was pretty much no doubt that MacKinnon would win it eventually - but it's a bit surprising that it came so soon, considering he's at the height of his career. He's only published four papers this year, but they're all Science or Nature (including one cover article). We can probably expect equally terrific work from him in the future.
I interviewed with him earlier this year (I applied to Rockefeller largely because of his lab), and he's one of the most intensely brilliant people I've ever met. There are very few scientists who will master a completely different technique in the middle of their career, while working on the same area of research. Fewer still are able to dominate the field. When I took physiology in college, we read multiple articles which described hypotheses proved by a single figure in one of MacKinnon's papers.
(There are actually an increasing number of membrane protein structures available, some of them quite large. However, ion channels are apparently especially difficult to study, and none were solved before MacKinnon started.)
what? what the hell are you talking about? whats a multispan transmembrane protein structure?
Ok, a protein is.. well a protein.. little things that do simple tasks in the body. Kind of like computer programs.
The problem with proteins, is that even though we have the 'source code', (the sequence of amino acids forming the protein) we don't know what the things look like, since the chain can fold in a near-infinite number of ways. So it's important to figure out what the 3D-structure (positions of the amino acids) are.
That way, we can get clues as to how the thing works.
Now.. think of our cell.. it's like a computer, in the meaning that it contains lots of important data we want to keep safe. To stop anyone from getting in, we have a 'firewall'.. a cell membrane which stops intruders from getting in.
Of course, a computer which is completly firewalled is not very useful, nor is a cell. It needs stuff from the outside.
That's why we have these transmembrane proteins, which work as 'packet filters' and let molecules which are OK (like water, which is what Agre works with) in and out, but not suspicious, unwanted molecules.
The potassium-ion channels are even cooler, because the 'operating system' (intracellular signalling) can turn them on and off when needed.
Now a protein is a chain, right? So 'multispan' just means that the chain goes back and forth perpendicular to the membrane multiple times.
Wow, way to make the headline inaccessible to anyone without a huge interest in biology... Basically MacKinnon solved the folding of extremely hard to study protiens in the cell membrane that allow ions into the cell. The cell membrane is non-polar (oily), while water is polar. These proteins exist so water, metal ions, etc. can get into the cell. What makes these protiens so hard to study is that when you try to remove them from the cell membrane to study them they turn inside out! The polar inside of the protein (which lets the polar stuff in) is attracted to the water, while the non-polar outside, normally attracted to the cell membrane, gets folded up to the inside (never knew a molecule could turn inside out before...).
This kind of research has huge applications to medicine, since most drugs/poisons/anything not fatty have to enter the cell through these pores. I am wondering whether he used distributed or parallel protien folding simulations for some of his work... X-ray crystallography on globular protiens usually yields poor results (it is hard to get the X-rays to diffract to show the inner channel structure) compared to crystalline/regular protiens.
The first transmembrane protein structure was over 20 years ago, in 1982 (the photosynthetic reaction center, by Hartmut Michel). There have been 10-20 since, not lots, but NOT the first. Saying this is the first transmembrane protein structure is like saying SCO invented Unix. or something. The reason this is important is because McKinnon solved the first Potassium Channel membrane structure, which is a very important protein for channeling ions across the membrane (used in transmitting nervous signals).
I think, therefore I thought.
... along with Hartmut Michel and Robert Huber to solve the crystal structure for a multi-pass transmembrane protein (bacteriorhodopsin). They, too, were awarded the Nobel Prize for their stunning work in 1988. MacKinnon's was for being the first to solve the structure of a protein that had remained elusive for so long and that had such critical biological relevance.
I am willing to bet that it or other distributed computing projects are actually quite critical in the types of work represented by this Nobel prize.
Nope. Refinement of structures often uses molecular dynamics, one of the classical simulation methods and also a (very slow) way of looking at protein folding. However, the software that does this is single-processor and actually doesn't require too much more power than a fast desktop. These structures were all at around 3-Angstrom resolution, and once you're able to collect and properly phase X-ray data of that quality, the global structure is obvious.
Everything that was known or guessed about membrane channel structures before this work was done using electrophysiology and classical molecular biology - purely experimental methods, both quantitative and qualitative. Relatively few structural biologists use standalone simulations, and this is only ever done after a high-resolution structure has already been obtained. The only people using de novo simulations are those working on protein folding (most of whom are actually experimentalists) or protein design people.
I know of no important native biological structure solved with the aid of prior simulation; this is not to say that none exist, but you're grossly overestimating the importance of theoretical methods.
Proteins are biological polymers that are produced in living cells; they are composed of amino acids whose sequence is translated from DNA. The reason why the genome is of such great interest is that proteins provide the "molecular machinery" of the cell, to put things crudely; the genome provides a blueprint on how to assemble proteins, and the diversity of proteins gives rise to much of the cellular functionality essential for life.
Determining the 3D structure of proteins is a very hard but essential part of learning how they work. Unfortunately, knowing the sequence of a protein (which you can derive from DNA) only gives hints about the 3D structure. There are a number of large computational projects such as Folding@Home and Blue Gene that are devoted to predicting protein folding from a 1D sequence of amino acids to a 3D structure.
X-ray crystallography is the traditional way of determining the structure of proteins; you basically analyze the diffraction pattern of X-rays from a crystal of the protein of interest.
Now to your question: a multispan transmembrane protein is a protein that typically sits in the cell membrane that encloses the cell (alternatively, there are other internal membranes as well). Most of these proteins pass through the membrane several times, back and forth. These proteins are very important because they are involved in cell signalling and transport of substances into and out of the cell; ion channels are a prime example of transmembrane proteins. But transmembrane proteins are also notoriously difficult to study and crystallize because they do not solubilize without detergents, and are challenging to reconstitute in their native form.
If you look in the Protein Data Bank, there are lots of proteins that have been crystallized; but only a very small portion of them are transmembrane. This year's Nobel prize in part recognizes advances in studying the structure and function of these important proteins.
Get Cn3D here and then look at the potassium channel here in 3D.