Hidden 3-D atomic structure revealed – drugs for Alzheimer’s a step closer

A new study involving shooting X-rays at crystals has uncovered the precise three-dimensional structure of an enzyme associated with Alzheimer’s disease, allowing researchers to now use powerful computers to discover drug-like molecules to treat the disease. 

The X-rays were produced by the Australian Synchrotron at Clayton which acts like a giant X-ray microscope. 

When researchers started the project in 2021 the enzyme called PLD3 was already associated with Alzheimer’s disease through a genetic study of Alzheimer’s patients said Professor Michael Parker, Head of Structural Biology at St Vincent’s Institute of Medical Research in Melbourne, SVI. 

“We determined the PLD3 structure atom-by-atom and discovered it was quite different from other PLD family members. The structure was used to understand how genetic mutations associated with Alzheimer’s disease impact on the structure and function of the enzyme”. 

“This structure is highly significant as it gives us an edge in discovering molecules that will modulate the activity of the enzyme that might be developed into drugs”. 

“We produced sufficient pure quantities of the enzyme from mammalian cells, inducing it to form crystals and then shooting X-rays at the crystals to reveal the atomic structure of the enzyme,” said Professor Parker.

Despite Alzheimer’s disease being discovered more than a century ago, drugs are only starting to appear over the last year that have a small effect on slowing down cognitive decline albeit with troubling side-effects.  A prevailing thought in the field is that the disease will need to be treated successfully using a combination of drugs.  

“Our PLD3 discovery is a first step in developing novel drugs that could be given in combination with drugs being developed against other targets. Furthermore, the cellular location of PLD3 suggests it could be a target for other dementias like Lewy Body Dementia,” said Professor Parker. 

The leading-edge work published in The FEBS Journal was performed by Japanese Masters student, Kenta Ishii, with mentoring from lab members. Some of the key experiments to characterise the protein were performed by PhD student Marialena Georgopoulou. 

The FEBS Journal is an international peer-reviewed Journal devoted to publication of high-quality papers reporting significant advances in the molecular life sciences.