World first Monash research unveils a key villain in migraine

In a paper published today in the prestigious journal Nature, researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) led by Doctor Lynn Liang, Doctor Denise Wootten and Professor Patrick Sexton have solved a key piece of the puzzle surrounding migraine, revealing for the first-time molecular details of one of the key initiators in migraine headaches.

Migraines affect approximately two million Australians, and are characterised by symptoms including pain, nausea and poor sleep. They account for nearly three percent of all time lost to disability.

A key player in the initiation, and pain, of migraines is a neuropeptide called calcitonin gene-related peptide (CGRP). In order to generate the pain response, CGRP must interact with a particular receptor in the brain. However, there is an added level of complexity because this particular receptor is unusual: it will not respond to CGRP unless another “partner protein” is present.
Very recently, the first drug to prevent migraines was approved. This drug, Amovig, acts by binding to the CGRP receptor to block CGRP interacting with its target.

This study presents the first high-resolution structure of the activated CGRP receptor, together with CGRP and its main signal-transmitting partner.
The study’s findings are a major breakthrough for understanding how the selectivity of receptors can be controlled by novel protein partners.

“Our work, solving the structure of activated receptor complex, allows design of novel drugs that can activate the receptor,” said Dr Denise Wootten.

“Excitingly, the CGRP receptor is not just a villain, but can also be activated for beneficial outcomes. For example, there is accumulating evidence that activation of the receptor could be used to treat inflammatory bowel disease, or resistant hypertension”.

“The CGRP receptor structure is the first example where we have been able capture a snapshot of a receptor that has this complex mechanism of action, one that is vital to the control of many physiologically important receptors,” Professor Sexton said. “It provides key insight into why drugs targeting this class of multi-domain proteins have been difficult to develop.”

The research was a multi-disciplinary, international collaborative effort driven by MIPS researchers, with key contributions by collaborators at the Max Planck Institute of Biochemistry in Germany, the University of Essex in the UK, the University of Auckland in New Zealand, Fudan University in China, and the Mayo Clinic in the US.

MIPS Director, Professor Christopher Porter said “this research could pave the way for novel drug development in areas of ongoing therapeutic need.”

“Professor Sexton and Doctor Wootten have provided unique insight into the activated form of the CGRP receptor. Perhaps most importantly it sets the fundamental framework for the development of next generation medicines that interact with this critical disease target.”

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