Protein crystallography at BESSY II: A mighty tool for the search of anti-viral agents

nCoV-CDC
Coronavirus: A novel coronavirus (SARS-CoV-2) is spreading worldwide and can cause severe respiratory symptoms (COVID-19).  © CDC/Wikimedia commons

BESSY II is a highly brilliant X-ray light source for research. With its special X-ray light we can also examine proteins that play an important role in viruses, bacteria or cells.

The building blocks of life: proteins

Proteins are involved in all processes in living organisms. They are huge molecules (macromolecules), which are made up of hundreds of amino acids and display a highly complex three-dimensional architecture. Parts of these macromolecules are folded, others look like loops or spirals. This 3D architecture is crucial for the function of the protein.


How does protein crystallography work?

Pilatus detector for crystallography

At BESSY II three beamlines are specialized for protein crystallography. There the 3D architecture of proteins can be decoded. These beamlines are also called MX beamlines, M stands for „macromolecular“ and X for „X-ray structure analysis“.  

In the first step, protein crystals are grown out of a solution so that the macromolecules arrange themselves on regular lattice sites. This procedure requires a lot of experience. Protein crystals are extremely tiny and fragile. A team from the MX group at HZB has developed a special sample holder to make the handling of these delicate crystals much easier.

In the second step, the samples are cooled in liquid nitrogen and then gradually held in the X-ray beam by a robotic arm. The X-ray light is diffracted at the protein crystal structure and the diffraction pattern is registered by a detector.

In the last step, every single spot of this diffraction pattern is analyzed. With the help of sophisticated algorithms, the 3D architecture of the protein can thus be decoded. In addition, a computer program also calculates the electron density around the protein molecule, which contains important information about binding options and chemical properties of the protein.

Which protein of the SARS-CoV-2 virus was investigated at BESSY II?

Corona Virus Protease Ribbon Surface

Schematic representation of the coronavirus protease. The enzyme comes as a dimer consisting of two identical molecules. A part of the dimer is shown in colour (green and purple), the other in grey. The small molecule in yellow binds to the active centre of the protease and could be used as blueprint for an inhibitor. © HZB

The main protease of the SARS-CoV-2 virus was studied at BESSY II. This protein is essential for the reproduction of the virus. The chemist Prof. Dr. Rolf Hilgenfeld carried out these investigations on BESSY II in order to identify suitable targets for an active substance (inhibitor).

Why is protein crystallography so important for drug development?

Like a key in a lock, the active ingredient has to fit exactly in order to obstruct the actual function of the protein. Many proteins and/or enzymes are studied at BESSY II with the aim of developing such active substances.

The MX team also provides a high-throughput method for this purpose, which can be used to systematically test hundreds of drug fragments in protein crystals. Such drug building blocks can then be used to develop effective therapeutics much faster.

What can BESSY II contribute?

BESSY II

BESSY II

Research on big challenges has the highest priority. We provide tools and expertise to advance the work on SARS-CoV-2 and identify potential weaknesses of the virus.  All data and results are immediately available to the entire scientific community so that active substances can be developed as quickly as possible. Drug development does not take place at BESSY II itself, but at other research institutions. At BESSY II, however, we can offer some mighty tools to accelerate this process.