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Drug Developers Turn to Advanced Crystallography Techniques for Critical Structural Information

By LabMedica International staff writers
Posted on 24 Dec 2012
The three-dimensional structure of the enzyme cathepsin B was established within intact cells of the protozoan parasite Trypanosoma brucei by researchers employing an intensely powerful free-electron X-ray laser. More...


T. brucei causes African sleeping sickness, a disease that threatens more than 60 million people in sub-Saharan Africa and annually kills an estimated 30,000 people. Currently no good drug solutions exist for treatment of the disease. The enzyme cathepsin B is among the potential targets for drugs under development. However, methods used so far to study the structure of the mature, active form of cathepsin B have not provided sufficient information for the design of a safe and specific drug against the parasite.

In the current study investigators at Arizona State University (Tempe, USA) and their colleagues at the University of Hamburg (Germany) and the University of Lübeck (Germany) combined two recent innovations, in vivo crystallization and serial femtosecond crystallography, to obtain the room-temperature 0.21 nm (2.1 Angstrom) resolution structure of the fully glycosylated precursor complex of cathepsin B.

To obtain this unprecedented resolution the investigators used the free-electron laser Linac Coherent Light Source (LCLS) at the [US] National Accelerator Laboratory SLAC (Palo Alto, CA, USA). This intensely powerful light source allowed the structure of the enzyme to be determined from one micrometer-sized in vivo crystals. An aqueous suspension of enzyme crystals was passed through the path of the laser beam, which fired approximately 120 times per second. On average, every eleventh shot impacted a crystal, resulting in a total of 293,195 diffraction images being recorded.

This huge number of images could only be processed by massive parallel computing, to first generate a three-dimensional map of all diffracting signals from which an image of the enzyme structure was calculated. The final result, which was published in the November 29, 2012, online edition of the journal Science, revealed the enzyme's structure with a resolution of 0.21 nm.

"These images of an enzyme, which is a drug target for sleeping sickness, are the first results from our new "diffract-then-destroy" snapshot X-ray laser method to show new biological structures which have not been seen before,” said contributing author Dr. John Spence, professor of physics at Arizona State University.

“This paper is so exciting as it is based on nanocrystals grown by the groups at in Hamburg and at the University of Lübeck inside living insect cells,” said contributing author Dr. Petra Fromme, professor of chemistry and biochemistry at Arizona State University. “This is the first novel structure determined by the new method of femtosecond crystallography. The structure may be of great importance for the development of new drugs to fight sleeping sickness, as it shows novel features of the structure of the cathepsin B protein, a protease that is essential for the pathogenesis, including the structure of natural inhibitor peptide bound in the catalytic cleft of the enzyme.”

Related Links:

Arizona State University
University of Hamburg
US National Accelerator Laboratory SLAC



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