Protein crystallography at BESSY II: faster, better and more and more automatic

Many diseases are linked to malfunctions of proteins in the organism. The three-dimensional architecture of these molecules is often highly complex, but it can provide valuable insights into biological processes and the development of drugs. X-ray diffraction at the MX beamlines of BESSY II can be used to decipher the 3D structure of proteins. To date, more than 5000 structures have been solved at the three MX beamlines. Here, we present a review and an outlook with  Manfred Weiss, head of the research group for macromolecular crystallography. 

How do you look back on the past years?

Manfred Weiss: The beamlines for macromolecular crystallography came into operation in 2003 under the leadership of Uwe Mueller. In the early years, solving a structure took much longer. Everything was done manually. After ten years, we had solved the first 1,000 structures. It then took us only three years to solve the next 1,000, and this trend continued. The first setback came with the arrival of the coronavirus pandemic. No one was allowed to travel anymore. This motivated us to develop options for remote measurements more quickly. Then, in mid-2023, a cyberattack paralysed HZB's IT systems. This was a major setback. However, we overcame it, and by the end of 2025, we had decoded the 5,000. structure.

Why is it so important to know the 3D structures of certain proteins?

Proteins are huge molecules that can have spiral, branched or ladder-like structures, as well as pockets and channels. It is this architecture that enables proteins to perform certain functions in biological systems. If a foreign molecule binds to a specific site on the protein, it can alter or disrupt this function. However, for this to happen, the active molecule must fit quite precisely into the protein structure, like a key in a lock. This is why the 3D architecture of proteins is exciting not only for basic research, but also for searching for active substances to combat diseases.

Which structures have left a lasting impression on you?

We have solved the structures of many important molecules, for example proteins that play a role in certain cancers and proteins from the SARS-CoV-2 virus. We have also deciphered the structure of a bacterial enzyme that can break down the plastic PET into basic building blocks when used together with another enzyme. Plant proteins have also been studied here, which reveal something about how plants perceive their environment. However, I am particularly proud that we have built up a new substance library in collaboration with the Drug Design Group at the University of Marburg. This library contains 1,103 organic molecules that can be used as building blocks for new active substances. The HZB substance library is available worldwide for research and is also being used in the search for active substances against SARS-CoV-2.

What is your current setup?

Our three beamlines are equipped with state-of-the-art hybrid pixel detectors that capture data at lightning speed and with virtually no noise. We can now measure ten times more samples in the same amount of time than was previously possible. We have robotic arms on two of the beamlines to change the samples. This allows us to examine hundreds of samples in series. More than a hundred international user groups from the fields of science and pharmaceuticals use our facilities.

And your plans for the future?

We are continuing to expand automation and are working on accelerating the evaluation process with the help of AI tools. In the near future, when BESSY II+ delivers an even more intense X-ray beam, we hope to be able to offer time-resolved measurements and directly observe how molecules interact with proteins.

Thank you for the conversation!