Structural biology elevates basic research to a higher plane

​Proteins are a cutting-edge target for scientists working in many areas of life sciences because they are
at the core of the most basic processes of living things. In 2012, Brian Kobilka and Robert Lefkowitz were
awarded the Nobel Prize in Chemistry for the discovery of G protein-coupled receptors, and our own Jan
Steyaert (VIB-VUB) and his colleagues played an important role in this groundbreaking structural biology
research – demonstrating VIB’s front-running position in this field. Let’s have a look at other innovative
projects conducted by VIB scientists that feature structural biology approaches to studying proteins.

Proteins, fundamental and dynamic building blocks of life as we know it, hold huge potential when it comes to understanding vital cell processes and treating diseases. VIB structural biologists Han Remaut (VIB-VUB) and Wim Versées (VIB-VUB), together with cell biologist Patrik Verstreken (VIB-KU Leuven), are hard at work conducting basic research on proteins with the potential to have far-reaching effects, especially when it comes to treating neurodegenerative diseases and epilepsy, or developing nonantibiotic therapies for infection.

“Wim and I studied together,” explains Patrik (VIB – KU Leuven). “Later on, after discussing our research interests, we discovered that while our expertise in neurology and structural biology are totally complimentary, there is also a lot of overlap in terms of the biological questions we were seeking answers for.” Wim Versées, staff scientist in the Jan Steyaert lab (VIB – VUB), concurs and adds: “We’re driven by our
commitment to understanding biological processes in all their details, even down to the atomic level.”

Structural biology gives scientists immediate visual insights into the atomic structure of proteins, leading to new hypotheses concerning their functions in cells and the way in which, for example, mutations can lead to
certain diseases. Patrik and Wim initially began their collaboration by studying a protein named ELP3,
which is implicated in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. More recently, they’ve been investigating an epilepsy-linked protein called TBC1D24/Skywalker, publishing a paper revealing their insights in the leading journal Nature Structural & Molecular Biology.

For Han Remaut (VIB – VUB) the atomic understanding of protein structures has fascinated him since the very beginning of his studies. “Each protein can be seen as a unique model, sensor or molecular machine with properties that capture the imagination,” says Han poetically. In collaboration with a crossborder team of scientists, Han investigated how the E. coli bacterium is able to bind to the surface proteins of bladder cells,
avoiding antibiotics and leading to pain and tissue damage. Targeting this binding mechanism is a potential way for new nonantibiotic therapeutic drugs to fight bladder infections. A similar approach was used to identify non-antibiotic methods of fighting Helicobacter pylori infection, one of the leading causes of gastritis
and ulcers, and a possible cause of stomach cancer. His research on E. coli was published in Cell Host & Microbe, and two lines of discovery on H. pylori were published in Nature Microbiology and Cell Host & Microbe.

Han’s study of bacterial protein binding mechanisms and Wim and Patrik’s research on TBC1D24/ Skywalker are great examples of how a structural biology approach to the investigation of proteins led to medically-applicable insights. “The vast majority of our medications act upon proteins. A detailed picture of their structures and functions very often has direct medical relevance, with structural insights at the molecular level enabling us to understand how drugs work, or providing us a lead to new ones,” Han says.

“We study the structures of proteins to ask very specific questions,” Wim continues. For example, understanding the structure of Skywalker gives insights to Patrik and his team into how pathogenic
mutations lead to epilepsy. “We can see the ways in which the mutations affect different sites on the proteins,
enabling us to formulate hypotheses that address the pathogenic and functional mechanisms of these proteins. That’s how we discovered a new mechanism in epilepsy and a way to suppress the defects that lead to the disease.”

The scientists enthusiastically anticipate the next steps: Wim and Patrik’s findings have identified a target, an enzyme that breaks down lipids in the brain. And although motivated, Han describes the translation of his insights into real drugs as a “long and uncertain road”. So, what happens next?

Based on the structure of the Skywalker protein, Wim and Patrik’s teams will determine specific inhibitors and develop assays that can be used to test how effective the inhibitors are. “We’re also going to continue to sift through the biology of Skywalker to look for other targets that we can inhibit to suppress epilepsy,” Patrik concludes. “This research demonstrates very clearly that basic science is of the utmost importance,” Wim
asserts. Even though the team’s initial aim was to understand the mechanisms and processes that form the foundation of Skywalker’s involvement in epilepsy, their results led to new avenues for the development of epilepsy therapies. “It’s incredibly motivating and serves an incentive to keep going even faster and harder,” he says.

Fischer et al, Nature 2016
Conover et al., Cell Host Microbe 2016