'Crystal engineering' to improve drug design

Related tags Amino acid Protein

A new technique for engineering protein crystals is helping
scientistsfigure out the three-dimensional structures of some
important biological molecules, including a key plague protein
whose structure has eluded researchers until now.

The technique promises to help pharmaceutical companies develop more effective drugs to treat various diseases by tailor-making molecules to 'fit' a protein's shape.

The development team, from the University of Virginia, US, report in the April issue of Structure​ that they were able to coax certain proteins to crystallise by carefully altering their surfaces using 'targeted mutagenesis'.

"In effect, the technique substitutes a small amino acid forcertain large ones. This effectively shrinks bulky groups of atoms onprotein surfaces that might otherwise prevent the proteins fromcrystallising,"​ said Zygmunt Derewenda.

"In order to determine a high-resolution structure of a protein, we need to study it in its crystal form. Yet many proteins do not crystallize easily, or even at all, with current laboratory techniques,"​ he explained.

"Using our approach, we can now make some of these proteins more amenable to crystallization without seriously affecting their overall structure or function."

The technique has already helped solve the structures of some particularly stubborn proteins, including the so-called V antigen ofYersinia pestis​, the bacterium that causes the plague. Despite numerous attempts, researchers had been unsuccessful in unlocking the secrets of this protein, which plays a key role in the bacterium's ability to cause the plague.

Working with Derewenda's group, David S. Waugh, of the USNational Cancer Institute was able to crystallise the protein and then determine its structure by X-ray diffraction. (The results were published in the February 2004 issue of Structure​.)

Other large biological molecules whose structures were recently solvedthanks to the new technique include an important protein complex containing ubiquitin, which is involved in a wide range of cellular processes. The technique was also used by a team at Merck Research Laboratories to yield a much more accurate structure of a potential anticancer drug target called insulin-like growth factor-1 receptor.

The research received funding from the the US government's National Institute of General Medical Sciences' Protein Structure Initiative (PSI), a 10-year project launched in 2000, which is aimed at dramatically reducing the time and cost of solving proteinstructures.

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