In brief

The transmembrane domain of the SARS-CoV-2 spike protein, a crucial component for viral infectivity, forms a helical structure in detergent micelles as seen using nuclear magnetic resonance spectroscopy.

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Fine-grained anatomy of a viral enemy

16 Nov 2023

Investigations into an under-explored region of SARS-CoV-2's spike protein reveals detailed structural insights that can represent valuable drug targets.

They say you should keep your friends close and your enemies closer. By that logic, scientists say the more we know about viruses—down to their intricate molecular structures—the better we’ll be at defeating them.

Congbao Kang, a Group Leader of the Structural Biology team at A*STAR’s Experimental Drug Development Centre (EDDC), explained that until now, most drug discovery efforts to combat SARS-CoV-2 have focused on the N-terminal region of the virus’ spike protein, for its role in gaining entry into host cells.

However, because the spike protein is particularly prone to mutations, these treatments can eventually be rendered ineffective.

Kang’s team took a divergent approach, zeroing in on a specific part of the spike protein called the transmembrane domain (TM) instead. Thought to provide both flexibility and stability to the spike protein, TM domain's dynamics during COVID-19 infections have remained elusive.

“The structural analysis of TM proteins can be challenging due to the nature of the transmembrane regions,” said Kang. “To effectively study these proteins, it is necessary to use membrane-mimicking systems that replicate their native environment.”

In their study, Kang and colleagues collaborated with a researcher from the Guangdong Academy of Sciences, China, to analyse the TM structure at high resolution with the help of microscopic ‘bubbles’ called micelles. These contain both water-loving and water-repellent environments that mimic the lipid bilayers of human cell membranes and help stabilise the TM proteins.

After visualising the TM-containing micelles using nuclear magnetic resonance spectroscopy, Kang’s team observed that the viral protein formed a characteristic helical structure. They also identified a linker that acted like a flexible bridge between the TM helix and HR2 region in the spike protein.

In addition to these never-before-seen glimpses of the TM domain’s architecture, the team also identified particular regions of the protein that can bind to small molecules—a feature which can be crucial for developing antiviral therapies.

The team is currently deploying alternative membrane systems to examine the delicate complexity of TM structures. Kang’s team is also interrogating mechanisms in which small molecule inhibitors can bind to the TM domain to inhibit the infectivity of the SARS-CoV-2 spike protein.

The A*STAR-affiliated researchers contributing to this research are from the Experimental Drug Development Centre (EDDC).

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Li, Q., Huang, Q. and Kang, C. Secondary structures of the transmembrane domain of SARS-CoV-2 spike protein in detergent micelles. International Journal of Molecular Sciences 23 (3), 1040 (2022). | article

About the Researcher

Congbao Kang obtained his PhD from Nanyang Technological University, Singapore where he was awarded the prestigious Singapore Millennium Foundation (SMF) PhD scholarship. Following his postdoctoral study at Medical School of Vanderbilt University, he received the A*STAR Investigatorship award and joined A*STAR as a Group Leader in 2009. He utilises solution NMR spectroscopy to uncover the structures and dynamics of membrane proteins, including ion channels and receptors, as well as proteins from viruses such as Dengue, Zika, and SARS-CoV-2. His team also conducts fragment screening and explores macromolecule-ligand interactions to drive forward drug discovery efforts. He co-founded Ligature Therapeutics to develop novel protein degraders. Presently, he leads the structural biology team at EDDC, focusing on understanding the mechanisms of action of diverse drug modalities through the application of structural and biophysical techniques such as NMR, X-ray and Cryo-EM with aims to facilitate target-based drug design for developing innovative pharmaceuticals.

This article was made for A*STAR Research by Wildtype Media Group