#SynchroLightAt75 – From the Ribosome to CRISPR

Structural Biology at the ALS: From the Ribosome to CRISPR

Since the first protein crystallography beamline came online here in 1997, thousands of protein structures have been solved at the Advanced Light Source (ALS). One of the earliest high-profile structures was that of the full ribosome complex, where all the proteins necessary for life are produced based on RNA blueprints. The results reinforced the impression that the ribosome is a dynamic molecular machine with moving parts and a very complicated mechanism of action. More recently, the ALS has contributed to a greater understanding of programmable CRISPR proteins such as Cas9. In contrast to earlier genome-editing tools, Cas9 transforms the complicated and expensive process of gene editing into something simpler and more routine, like applying a genetic plug-in. In 2020, Jennifer Doudna and Emmanuelle Charpentier were awarded the Nobel Prize in Chemistry for “the development of a method for genome editing.”

Read more in the links below:


J.H. Cate et al., Science 285, 2095 (1999)

M. Jinek et al., Science 343, 1247997 (2014)

Press release: The Nobel Prize in Chemistry 2020

ALS highlights:

Solving the Ribosome Puzzle
Intriguing DNA Editor (CAS9) Has a Structural Trigger

Jennifer Doudna and the Nobel Prize: The Advanced Light Source Perspective

Antibody rigidity regulates immune activity

Scientists at the University of Southampton have gained unprecedented new insight into the key properties of an antibody needed to stimulate immune activity to fight off cancer, using the ESRF’s structural biology beamlines, among others.

The interdisciplinary study, published in Science Immunology, revealed how changing the flexibility of the antibody could stimulate a stronger immune response. The findings have enabled the team to design antibodies to activate important receptors on immune cells to “fire them up” and deliver more powerful anti-cancer effects. The researchers believe their findings could pave the way to improve antibody drugs that target cancer, as well as automimmune diseases.

In the study, the team investigated antibody drugs targeting the receptor CD40 for cancer treatment. Clinical development has been hampered by a lack of understanding of how to stimulate the receptors to the right level. The problem being that if antibodies are too active they can become toxic. Previous research by the same team had shown that a specific type of antibody called IgG2 is uniquely suited as a template for pharmaceutical intervention, since it is more active than other antibody types. However, the reason why it is more active had not been determined. What was known, however, is that the structure between the antibody arms, the so called hinges, changes over time.

This latest research harnesses this property of the hinge and explains how it works: the researchers call this process “disulfide-switching”. In their study, the team analysed the effect of modifying the hinge and used a combination of biological activity assays, structural biology, and computational chemistry to study how disulfide switching alters antibody structure and activity.

Read more on the ESRF website

Image: Flexibility of the monoclonal antibody F(ab) arms is conferred by the hinge region disulphide structure

Credit: C. Orr

#SynchroLightAt75 – Photon Factory at the dawn of structural biology using SR

The Photon Factory opened its first dedicated protein crystallography beamline with a Weissenberg camera in the mid-1980s. Prof. Ada Yonath, who was awarded the Nobel Prize in Chemistry in 2009 for her work on the structure-function analysis of ribosomes, was working at the Photon Factory at this time. The cryo-crystallography developed at the time led to the successful structural analysis.

Read more about the 2009 Nobel Prize in Chemistry and KEK’s Photon Factory here: KEK feature article

Image: Cryo-cooling system developed by Prof. Ada Yonath installed at the Photon Factory

Credit: Photo courtesy of Prof. Noriyoshi Sakabe

Cecilia Rocchi’s #My1stLight

#My1stLight memory at the SOLEIL synchrotron in Paris (PROXIMA-1 beamline) during my first year of PhD! So fascinated by the robotic arm, the collector of loops in liquid nitrogen and to see the place where our crystals diffract (although not always ^^’’) and the coveted three-dimensional structures born. I will never forget it! 😊

You never forget the first time, it was a real adventure. I ‘shot’ the crystals we had transported from Lyon with X-rays, and I also remember very well the first time I saw a high-resolution diffraction: even though it was not ‘my’ sample I was so happy! Since then, my adventure with structural biology has become a real love affair ♥

Image: Cecilia Rocchi on the PROXIMA -1 beamline at SOLEIL

Great minds think alike!

Marion Flatken from BESSY II & Luisa Napolitano from Elettra give advice to those at the start of their careers

Our #LightSourceSelfies campaign features staff and users from 25 light sources across the world. We invited them all to answer a specific set of questions so we could share their insights and advice via this video campaign. Today’s montage features Marion Flatken from BESSY II, in Germany, and Luisa Napolitano from Elettra, in Italy. Both scientists offered the same advice to those starting out on their scientific journeys: “Be curious and stay curious”. Light source experiments can be very challenging and the tough days can lead to demotivation and self-doubts. In these times, it is good to seek out support from colleagues, all of whom will have experienced days like this. Even if you think you can’t succeed with your research goals, try because it is amazing what can be achieved through hard work, tenacity and collaboration.

Be curious and stay curious!

Luisa Napolitano is a staff scientist working in the structural biology lab at the Elettra Sincrotrone in Trieste, Italy.

In her #LightSourceSelfie, Luisa talks about switching from cellular biology to structural biology and how proud moments come when you solve a structure that you have been working on for years.

Her fantastic lab tour explains how the equipment enables you to prepare proteins for a range of experimental techniques, including crystallography, electron microscopy, SAXS and NMR. Luisa also explains why it is so valuable to have a structural biology lab located at the synchrotron where beamline staff are on hand to give you advice about your research.

Finally Luisa touches on the way her work as a scientist is helping to inspire her 9 year old son. She offers this advice to younger peers, “Be curious and stay curious! Don’t be afraid and try, even if you think something is too much for you. Try it because you never know. It was like me when I started in structural biology at the beginning, I was scared but at the end of the story I like structural biology a lot, and I don’t think I will change my field of action anymore.”