Nav: Home

New knowledge about the dynamics of proteins can shape the future in drug development

June 27, 2017

New research provides mechanistic insight into how protein dynamics control the activity of a group of enzymes called serine proteases. As serine proteases play pivotal roles in blood coagulation, the innate immune system and tissue remodeling, the results may be important for the development of new drugs for the treatment of various diseases.

Proteins are usually considered to have a stable three-dimensional structure with a well-defined folding of the peptide chain. However, the peptide chain seems to undergo small or large movements that constantly change the three-dimensional structure of the protein. These constant changes in the three-dimensional structure are termed protein dynamics. Although it is well-established that protein dynamics play a crucial role in the activity level of a group of enzymes called serine proteases, the mechanism behind these observations has remained elusive. As the activity level of serine proteases plays important roles in blood coagulation, the innate immune system and in tissue remodeling, protein dynamics thus become a crucial factor in the regulation of these vital physiological processes.

The new research, recently published in the highly recognized journal Nature Scientific Reports, provides a mechanistic insight into the protein dynamics that control the activity level in the serine protease urokinase. The researchers from Aarhus University have solved five different X-ray crystal structures of urokinase.

"Determining the crystal structures of urokinase was far from an easy task," says Postdoc Tobias Kromann-Hansen. "Urokinase is a super dynamic protein that constantly changes its three-dimensional structure. This complicates the formation of crystals," continues Tobias Kromann-Hansen. To solve this problem, the researchers from Aarhus University collaborated with researcher from The Vrije University of Brussels and Leuven University to develop a panel of camelid-derived antibodies that binds specifically to urokinase.

"The camelid antibodies have proven to be a very useful tool in X-ray crystallography as they tend to stabilize dynamic proteins, thus facilitating the formation of crystals," says Tobias Kromann-Hansen. The crystal structures gave the researchers five different snapshots of urokinase and revealed that the urokinase peptide chain undergoes surprisingly large movements. These movements were further mapped using a special technique, HDX-MS (Hydrogen Deuterium Exchange Followed By Mass Spectrometry), in which Professor Elizabeth A. Komives at the University of California, San Diego, is a world-leading expert. Compared with biochemical studies, the X-ray crystal structures and the HDX-MS data provided a detailed description of the molecular mechanisms that underlie the protein dynamics that control the activity level in urokinase.

The results provide a basic understanding of the mechanistic function of serine proteases. But the researchers hope that the results can open up for new possibilities in drug discovery and treatment of various diseases. Tobias Kromann-Hansen explains: "With these results, we have found that urokinase can exist in equilibrium between an active and an inactive state. We now know the form of the inactive state. By developing molecules that specifically recognize and stabilize the inactive state, we may shift the equilibrium towards the inactive state, thereby inhibiting the disease-promoting activity of urokinase in, for example, cancer and arthritis. Our hope is to find similar inactive states in other serine proteases in order to apply this principle in treating other serious diseases that involves a high serine protease activity level."
The research was supported by the Carlsberg Foundation through funds for Tobias Kromann-Hansen's postdoc at the University of California San Diego, as well as a grant from the Danish-Chinese Center for Proteases and Cancer, led by former professor Peter A. Andreasen from the Department of Molecular Biology and Genetics at Aarhus University.

Aarhus University

Related Protein Articles:

Memory protein
When UC Santa Barbara materials scientist Omar Saleh and graduate student Ian Morgan sought to understand the mechanical behaviors of disordered proteins in the lab, they expected that after being stretched, one particular model protein would snap back instantaneously, like a rubber band.
Diets high in protein, particularly plant protein, linked to lower risk of death
Diets high in protein, particularly plant protein, are associated with a lower risk of death from any cause, finds an analysis of the latest evidence published by The BMJ today.
A new understanding of protein movement
A team of UD engineers has uncovered the role of surface diffusion in protein transport, which could aid biopharmaceutical processing.
A new biotinylation enzyme for analyzing protein-protein interactions
Proteins play roles by interacting with various other proteins. Therefore, interaction analysis is an indispensable technique for studying the function of proteins.
Substituting the next-best protein
Children born with Duchenne muscular dystrophy have a mutation in the X-chromosome gene that would normally code for dystrophin, a protein that provides structural integrity to skeletal muscles.
A direct protein-to-protein binding couples cell survival to cell proliferation
The regulators of apoptosis watch over cell replication and the decision to enter the cell cycle.
A protein that controls inflammation
A study by the research team of Prof. Geert van Loo (VIB-UGent Center for Inflammation Research) has unraveled a critical molecular mechanism behind autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis.
Resurrecting ancient protein partners reveals origin of protein regulation
After reconstructing the ancient forms of two cellular proteins, scientists discovered the earliest known instance of a complex form of protein regulation.
Sensing protein wellbeing
The folding state of the proteins in live cells often reflect the cell's general health.
Protein injections in medicine
One day, medical compounds could be introduced into cells with the help of bacterial toxins.
More Protein News and Protein Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Warped Reality
False information on the internet makes it harder and harder to know what's true, and the consequences have been devastating. This hour, TED speakers explore ideas around technology and deception. Guests include law professor Danielle Citron, journalist Andrew Marantz, and computer scientist Joy Buolamwini.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at     You can read The Transition Integrity Project's report here.