Irish researchers generate crystal structure for a PEGylated protein

By Dan Stanton contact

- Last updated on GMT

Related tags: Protein

Irish researchers generate crystal structure for a PEGylated protein
Irish scientists have completed the most comprehensive structural study yet of a PEGylated protein, giving greater insight into how such molecules improve injectable therapies.

Protein PEGylation is a technique to improve the properties of injectable therapeutic proteins; PEG stands for ‘polyethylene glycol,’ a synthetic polymer that is attached to proteins. 

The PEG chain boosts a therapeutic protein’s size and retention in the bloodstream.  Since the 1970s, PEGylated proteins have improved the treatment of diseases such as hepatitis C, leukemia, Crohn’s disease and arthritis.

Yet the structure of the proteins remained elusive. Now, a group in NUI Galway in Ireland has generated the first crystal structure of a protein modified with a single PEG chain.  

Most people would say that it is impossible to crystallize a PEGylated protein​,” Peter Crowley, chemist in NUI Galway, Ireland, and senior author of the study​ in Nature Chemistry ​told this publication.

It behaves as a long random structure, something like a piece of spaghetti swirling around in sauce​.”

PEG is a synthetic polymer of chemical structure -CH2​CH2​O-. It can be made in different sizes and branched forms are possible.  Crowley explains why deciphering the structure matters.

There are still questions about how PEG increases the size of a protein and how PEG might stick to the protein surface. One model is that the PEG acts like a ‘shroud’ and wraps around the protein. In the alternative model known as "dumbbell" the PEG avoids the protein and behaves almost independently​,” Crowley said.  

Our crystal structure supports the [dumbbell] model. You might imagine the PEG is like a parachute dangling off the protein​.”

Protein Structure

The protein is structured as an orthogonal shaped structure with intertwined double helices and large pores that house the PEG chains.

The pores in the crystal are just the right size to accommodate the PEG. It seems therefore, that it might also be possible to engineer protein assemblies using PEG chains of different sizes​,” Crowley explained.

“EG does not have a three-dimensional fixed structure and so it is difficult to have a technique abel to visualize its conformation when is linked to a protein​,” said Gianfranco Pasut​, pharmaceutical scientist at the University of Padua in Italy.

“PEG has many positive effects, such protein half-life prolongation in vivo by reducing kidney clearance, but it usually reduces the protein activity as consequence to its steric entanglement towards the protein receptor​,” he added.

“Half-life prolongation and immunogenicity reduction are better with larger PEGs but also activity reduction is more marked with bigger PEGs. Knowing how PEG is structured around a protein will help the design of better conjugates.”

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