World first Monash Nature paper reveals active-state -cryo-EM structure of a vital drug target

In a paper published today in the prestigious journal Nature, researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) have presented the first high-resolution structure of an activated adenosine A1 receptor, bound to both its native activating ligand, adenosine, as well as its main “signal-transmitting” partner, the heterotrimeric Gi protein.

The adenosine A1 receptor is a member of the superfamily of G protein-coupled receptors (GPCRs), the largest class of all medicinal targets, and is linked to several diseases, including cardiovascular disease, cognitive dysfunction and chronic pain. Previous clinical trials focusing on drugs that can activate the A1 receptor for treatment of coronary conditions have failed because these drugs have not been selective enough to avoid undesirable side effects associated with actions at other protein targets.

The new MIPS research, which has ‘captured’ the structure of the receptor and its G protein in the process of being ‘switched on’ by adenosine now promises to overcome these drug selectivity limitations, as well as shed new insight into how this receptor works on a molecular level.

Lead researcher, NHMRC Senior Principal Research Fellow and Head of MIPS’ Drug Discovery Biology Theme, Professor Arthur Christopoulos said the study’s findings had significant implications for healthcare and drug discovery.

“Our results have exciting implications for future drug discovery. For the first time, we are now in a position to use atomic-level information to rationally develop new targeted medications to treat heart disease while minimising side effects,” Professor Christopoulos said.

“Understanding how this receptor is activated could also be applied to develop treatments for neuropathic pain in the future through more extensive research.”

This work was a multi-disciplinary effort driven by MIPS researchers including post doctoral fellow Mr. Christopher Draper-Joyce, Dr Alisa Glukhova and Professor Patrick Sexton, as well as key contributions by collaborators at the Max Planck Institute of Biochemistry in Germany and Monash University’s Department of Molecular Structural Biology.

The research was facilitated through use of novel technology termed “cryo-Electron Microscopy” (cryo-EM), a technique that was most recently acknowledged through the award of the 2017 Nobel Prize in Chemistry to its key originators. Cryo-EM involves firing beams of electrons at proteins that have been frozen in solution to identify their biomolecular structure.

“The promise of cryo-EM for illuminating new aspects of GPCR biology is only now starting to be realised, but the applications to novel drug discovery are clear and substantial,” Professor Sexton said.

The technology is currently being used by less than 10 per cent of researchers working in the field. Its promise is substantial, not only highlighted by the recent MIPS findings, but also because this week’s edition of Nature includes three other studies showing cryo-EM structures of other GPCR-Gi protein complexes.

MIPS Director, Professor Chris Porter commented “This work is a great example of the high impact, multidisciplinary research required to make substantive progress in drug discovery. Perhaps most importantly it sets the fundamental framework for the development of next generation medicines that interact with this critical disease target”.

The paper is available for viewing here

Contact: Divya Krishnan

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