1000th protein structure decoded at BESSY II

The inhibitor Ex-527 attaches to the enzyme Sirt-3 (shown here in light grey) and to acetylated ADP ribose; this substance is a product which results from Sirt-3 mediated deacetylation. This blocks the sirtuin’s active center to prevent further deacetylation. This way, the sirtuin has effectively set a permanent trap for itself the first time around. © C.Steegborn

In July of this year, the 1000th protein structure based on measurements obtained at BESSY II was published. The molecule in question belongs to a class of proteins called sirtuins, which are involved in aging, stress, and metabolic processes within the human organism. Bayreuth University’s Prof. Clemens Steegborn and his team uncovered a clever mechanism used by active substances to inhibit sirtuin activity. The results have been published in the renowned scientific journal Proceedings of the National Academy of Sciences, USA, and could potentially point the way to new cancer therapies.

It’s not only a protein’s composition but as well its conformation which matters. Ultimately, it’s a protein’s three-dimensional shape which offers clues as to what its job is and how it will ultimately interact with other molecules. Protein shape can be determined using X-ray  structural analysis – although proteins have to first crystallize for this to work. Analysis of these in most cases tiny crystals is dependent upon a source of extremely brilliant X-ray light and special measuring conditions like the ones that have been available for about a decade now at Bessy II’s MX beamlines. “Since 2003, we have a total of three MX beamlines here at BESSY II and researchers from all around the World come here to analyze their protein crystals,” says Dr. Uwe Müller, who originally set up the MX beamlines at BESSY II and who is also the man in charge of their scientific and instrumental maintenance.

Substantial measuring station improvements translate into dramatically improved performance
“Over the last few years, we have been able to improve the measuring station substantially, a fact which is reflected in the dramatic increase in performance we’ve seen!” As recently as 2010, Bayer Healthcare Pharmaceuticals Berlin researchers had decoded the 500th structure, a protein called PIM-1. “A mere two years later, in May 2012, the Steegborn group took the measurements, which have now led to publication of the 1000th structure,” says HZB scientist Dr. Manfred Weiss, who, together with Müller, is in charge of the MX beamlines. The vast majority of these published structures are coming out of publically funded research. True, scientists from industry do take advantage of the opportunities afforded by BESSY II but most industrial structures never end up seeing the light of day. As of February 2013, the new detector PILATUS-6M allows for even more highly precise insights into the complex conformations of these vital building blocks. “To our users, the PILATUS detector represents dramatic progress. Because of its size, noiselessness, and speed, PILATUS-6M is a true market leader in the field of X-ray crystallography detectors,” says Dr. Uwe Müller.

The 1000th structure offers medically relevant insights

Analysis of the 1000th protein is a particularly special highlight as the findings have potential relevance for medical research – because sirtuins regulate metabolism, the stress response and aging processes in the body and because a number of sirtuins (like Sirt-1 and Sirt-3) also play a role in oncogenesis. Targeted inhibition of their activity is viewed as an interesting approach to new cancer therapies. With their analysis, the research group around Prof. Dr. Clemens Steegborn at Bayreuth University was able to shed light on the ways in which an active substance, called Ex-527, suppresses Sirt-1 and Sirt-3 activity. “Our results show that Ex-527 is an inhibitor with an unusual and at the same time very sirtuin-specific mode of action,” explains Steegborn. “If we’re able to use what we’ve learned to specifically inhibit the activity of individual sirtuins, this could be one approach to an effective therapy with only minimal side effects.”

Celebration with award ceremony scheduled for October 16, 2013
On October 16, 2013, the MX beamline scientists will be celebrating their results with a symposium. Clemens Steegborn will also be receiving an award on that occasion.

To the paper in PNAS 2013; 8.-12. July
DOI: 10.1073/pnas.1303628110