How to generate trillions of useful proteins

Scientists from the University of California at San Diego (UCSD) have discovered a new way to generate trillions of proteins from a single organism. And their new protein copying technique will help to produce novel drugs.
Written by Roland Piquepaille, Inactive on

Scientists from the University of California at San Diego (UCSD) have discovered a new way to generate proteins. They found that a single organism, a virus that infects bacteria, called a bacteriophage, or phage, can produce 10 trillion varieties of a single protein via a single mechanism. This protein copying technique will give a new tool to drug researchers for "generating therapeutic enzymes and other medically important proteins to produce novel drugs."

The article of DrugResearcher.com is slightly different from this UCSD news release which starts like this.

A team led by UCSD biochemists has discovered the mechanism by which a simple organism can produce 10 trillion varieties of a single protein, a finding that provides a new tool to develop novel drugs.

So what did they find exactly?

Scientists from the University of California, San Diego, have detailed research in which a virus that infects bacteria -- called a bacteriophage, or phage -- can generate a kaleidoscope of variants of a particular protein.

The function of the massively variable phage protein is to tether the phage to the bacteria they infect. The phage "predator" protein fits into a "prey" protein on the bacteria like a three-dimensional puzzle piece.

Of course, this is not that simple. As the nature of proteins on the surface of bacteria changes, the phage has to create many variants of predator proteins to be successful. And this is not very common.

"This is only the second type of massively variable protein ever discovered," said Partho Ghosh, a professor of chemistry and biochemistry at UCSD who headed the research team.
"Only antibodies have more variation than this protein in phage. However, the genetic mechanism used by the phage to generate this diversity is completely different from that used by animals to produce antibodies, and has the advantage of giving the protein greater stability," he added.

So what was the first protein fold which could tolerate such massive sequence variations? It was the immunoglobulin fold.

And the new one, discovered at UCSD, is... the C-type lectin fold. And before going further, it's time to look at some images from the researchers.

Below is a figure showing the binding sites of some of the "major tropism determinant" (Mtd) variants studied by the scientists, which "greatly differ in their pattern of hydrophobicity. Mtd-P1 and Mtd-I& have highly hydrophobic binding sites, [while] the continuity of the hydrophobic surface decreases for Mtd-P3c." (Credit: UCSD) For more details about this figure, see below.

Nano helices -- part 2

The latest research work about this bacteriophage has been published as an "advance online publication" by Nature Structural and Molecular Biology under the title "The C-type lectin fold as an evolutionary solution for massive sequence variation " (September 18, 2005). Here are two links to the abstract and to the full paper (PDF format, 7 pages, 746 KB). The picture above was extracted from this paper, put online by one of the researchers.

I have no doubt that this discovery might be useful for developing new enzymes and drugs, but how much computing power will need these researchers to discover the chemical properties of several trillion proteins?

Sources: Wai Lang Chu, DrugResearcher.com, September 19, 2005; and various web sites

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