Nobel Prize – Lightsources.org

Unlocking the secrets of proteins

2024/10/112024/11/07

This year’s Nobel Prize in Chemistry goes to three researchers who have made a decisive contribution to cracking the code of proteins – important building blocks of life. However, developing applications from this knowledge, for example in medicine, requires research institutes such as PSI.

This year’s Nobel Prize in Chemistry came as a surprise in several respects. Firstly, only one of the three scientists chosen, David Baker, is a member of an academic research institution. The other two, Demis Hassabis and John Jumper, work at the Google subsidiary DeepMind. Secondly, the award is based on artificial intelligence (AI). And thirdly, the achievement being recognised draws on an Open Science project that would not have been possible without comprehensive, high-quality, open databases provided by the global scientific community – to which the Paul Scherrer Institute PSI is an important contributor. Given these unusual circumstances, it is easy to overlook the actual reason for awarding the prize. Yet that itself is revolutionary enough: The Nobel Committee is paying tribute to the three scientists for a breakthrough in protein research. Working at the company DeepMind, two of them developed an AI called AlphaFold which is able to predict the spatial structure of a protein with astonishing precision. This structure is a result of the way the molecule is folded, which in turn depends on the sequence of amino acids it contains.

Spatial folding is crucial

It is difficult to assess the full extent of the new possibilities offered by AlphaFold. Proteins and their spatial folding form the central basis of all biological systems – disrupting them can have fatal consequences. The form, function and activity of every single cell are controlled by proteins. This also holds true for the 30 trillion or more cells that make up the human body, or course, including the cells of the immune system and the brain, but also pathologically modified cancer cells. Some extra-cellular structures produced by cells are also made from proteins. These include collagen, which gives skin, bones, tendons and connective tissue their structure and strength. However, until recently scientists were often puzzled as to how the sequence of amino acids, which is relatively easy to determine, gives rise to the three-dimensional configuration.

To determine the spatial structure of proteins, which is crucial for their biological function, researchers had to resort to highly complex X-ray crystallography experiments, which often took years. Only in recent years has it become possible to achieve this by means of a particularly high-resolution form of electron microscopy. X-ray crystallography was first successfully used to determine the structure of a protein in 1959; the protein in question was myoglobin, the mussel protein which is responsible for intramuscular oxygen transport. The scientists led by Max Perutz, who was awarded the Nobel Prize for Chemistry in 1962, turned the protein into a crystal and sent monochromatic X-rays through it, similar to the radiation produced by Swiss Light Source SLS at PSI. The resulting diffraction pattern can be used to determine the folding of the protein chain – and thus provide information about the function of the protein. The location of active centres, for example, which interact with small molecules.

At the time that AlphaFold was developed, the structure of some 140,000 proteins had been determined experimentally. These are all listed in the Protein Data Bank (PDB), established in 1971, which is freely accessible to scientists and the general public. “More than five percent of the data it contains comes from the Swiss Light Source SLS at PSI,” says Jörg Standfuss, Head of the Laboratory of Biomolecular Research, which focuses on structural biology at the PSI Centre for Life Sciences. Most of the rest comes from other research centres that operate a high-quality X-ray source.

Read more on PSI website

Image: Proteins are involved in all life processes. They are made up of amino acid chains that form complex structures. This structure is crucial to the function of the proteins. That is why being able to predict the structure of a protein based on its amino acid sequence using AI is so important for understanding life and for innovation in medicine and biology.

Credit: hotspianiegra – stock.adobe.com

Congratulations to the Nobel Prize winners in chemistry

2024/10/112024/10/11

The researchers at the world’s largest free-electron laser, the European XFEL, are delighted that Demis Hassabis, John M. Jumper and David Baker have been awarded the Nobel Prize in Chemistry. The decoding of protein structures is an important field of research for X-ray lasers such as the European XFEL.

David Baker has been an active user of the European XFEL since 2022. His team has actively participated in single-molecule imaging experiments at the Small Quantum Systems (SQS) and SPB/SFX instrument.

There, they recorded diffraction patterns of computationally designed proteins and single molecules for the first time.

“We are excited that David Baker has received the Nobel Prize for his ground-breaking work in the computer-aided design of de novo proteins”, says Thomas Feurer, Chairman of the Management Board of European XFEL. “We look forward to collaborating on upcoming experiments where he plans to explore the ultra-fast dynamics and behaviour of these innovative proteins with us.”

Read more on European XFEL website

Image: David Baker, Demis Hassabis and John Jumper. Ill. Niklas Elmehed

Credit: Nobel Prize Outreach

SwissFEL: a next generation tool for Attosecond Science

2023/12/082023/12/20

The 2023 Nobel Prize in Physics was awarded for the development of attosecond science – a field that sheds light on the movement of electrons on their natural timescale. Several researchers at the Swiss X-ray free electron laser SwissFEL are recognised in the scientific background to this prize. This is no coincidence. With recent technical developments enabling attosecond and fully coherent X-ray pulses, SwissFEL promises to rapidly advance this emerging research area.

“We can now open the door to the world of electrons. Attosecond physics gives us the opportunity to understand mechanisms that are governed by electrons. The next step will be utilising them.” So said Eva Olsson, Chair of the Nobel Committee for Physics at the Royal Swedish Academy of Sciences, at the announcement of the 2023 Nobel Prize in Physics.

The prize was awarded to Pierre Agostini, Ferenc Krausz and Anne L’Huillier “for experimental methods that generate attosecond pulses of light for the study of electron dynamics in matter”. These breakthrough experimental methods are based on table-top laser systems – that is, laser systems that roughly fit onto an optical table and generate light mainly in the extreme ultraviolet energy range. Yet, in order to truly utilise our new insight into the world of electrons, further technological advances will be important that probe the movements of electrons in a wide variety of functional materials.

The scientific background produced by the Royal Swedish Academy of Sciences recognises the contributions from several researchers at PSI. There is a unifying theme to these researchers: they all now work at SwissFEL on upgrades that are enabling attosecond X-ray pulses, combining the possibilities of this astounding time resolution with the higher photon energies and higher photon fluxes offered by free electron laser light.

The contributions of these PSI researchers all lay in making the first steps of extending attosecond techniques, first developed in the gas phase, to new phases of matter – liquids and solids.

Read more on PSI website

Image: Contributions of a number of researchers at PSI were recognised in the scientific background to the 2023 Nobel Prize in Physics. These researchers include (L to R) Martin Huppert, Adrian Cavalieri and Stefan Neppl, all of whom are now working on the SwissFEL on advances that are enabling attosecond X-ray pulses. Here, they stand in the snow in the beautiful forest that surrounds SwissFEL.

Credit: Paul Scherrer Institute/Markus Fischer

#SyncroLightAt75 – Structure of the Ribosome

2022/12/012022/12/06

Along with Ada Yonath and Thomas Steitz,Venkatraman Ramakrishnan from the MRC Laboratory of Molecular Biology in Cambridge, UK was awarded the 2009 Nobel Prize in Chemistry for determining the structure of the ribosome, one of the largest and most important molecules in the cell. X-ray crystallography experiments that enabled elucidation of the ribosome structure used synchrotron light from a number of light sources worldwide, each with unique capabilities, including the Swiss Light Source SLS.

Read more on the PSI website

Image: Interior view of the experimental hall at the Swiss Light Source SLS

Credit: Photo: H.R. Bramaz/PSI

#SynchroLightAt75 – From the Ribosome to CRISPR

2022/10/112022/10/12

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.”

#SynchroLightAt75 – APS lights the way to 2012 Chemistry Nobel

2022/06/302022/06/30

Thanks in part to research performed at the U.S. Department of Energy’s (DOE) Argonne National Laboratory, the 2012 Nobel Prize in Chemistry was awarded today to Americans Brian Kobilka and Robert Lefkowitz for their work on G-protein-coupled receptors.

G-protein-coupled receptors, or GPCRs, are a large family of proteins embedded in a cell’s membrane that sense molecules outside the cell and activate a cascade of different cellular processes in response. They constitute key components of how cells interact with their environments and are the target of nearly half of today’s pharmaceuticals.

These medicines work by connecting with many of the 800 or so human GPCRs. But to do this well, a drug needs to connect to the protein like a key opens a lock. Improving drugs requires knowing exactly how these proteins work and are structured, which is difficult because the long, slender protein chains are folded in an intricate pattern that threads in and out of the cell’s membrane.

In a study performed at Argonne in 2007, Kobilka, a professor at Stanford University, used intense X-rays produced by the laboratory’s Advanced Photon Source (APS) to make the first discovery of the structure of a human GPCR. This receptor, called the human β₂ adrenoreceptor (β₂AR), is responsible for a number of different biological responses, including facilitating breathing and dilating the arteries.

Read more on the Argonne National Laboratory website

Image: This is an image of a G-protein-coupled receptor signaling complex whose structure was identified in 2011. The receptor is in magenta while the different G protein subunits are colored green, red and blue. Stanford biochemist Brian Kobilka shared the 2012 Nobel Prize in Chemistry for his work in determining the structure of this activated GPCR using X-rays provided by Argonne’s Advanced Photon Source.

#SynchroLightAt75 – Rod MacKinnon’s Nobel Prize in chemistry

2022/06/092022/06/09

Rod MacKinnon – Nobel Prize in chemistry 2003 for work on the structure of ion channels

The structural work of MacKinnon was carried out primarily at the Cornell High Energy Synchrotron Source (CHESS) and the National Synchrotron Light Source (NSLS) at Brookhaven. At the time, CHESS was a first-generation SR source. The award for MacKinnon’s work was the second recognition of SR work by the Nobel Committee. MacKinnon acknowledges the crucial role that the two synchrotron facilities, Cornell Synchrotron (CHESS/MacCHESS) and NSLS, have played in his research on the protein crystallography of membrane channels.

He said, `Without exaggeration that most of what is known about the chemistry and structure of ion channels has come from experiments carried out at these SR centres’.
Rod MacKinnon

Read more on the Nobel Prize website

Image: View showing the location of CHESS, which is underground at Cornell

Credit: Jon Reis

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

2022/05/272022/05/27

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