Enzyme structure that paves the way for new drugs in Parkinson’s disease


From left to right: Hanwen Zhu, Ph.D. Jisan, Ph.D.; and Dr. Patricia Hixon (all in St. Jude’s structural biology) have detailed structures of mutant enzymes known to cause Parkinson’s disease. I’ve decided. Credit: St. Jude Children’s Research Hospital

Structural biologists at St. Jude Children’s Research Hospital have determined the detailed structure of a mutant enzyme known to cause Parkinson’s disease. This achievement paves the way for research to develop new drugs that specifically target an abnormal form of protein enzyme called LRRK2.

Researchers led by Ji Sun, Ph.D. of St. Jude’s Department of Structural Biology today published their findings in the journal. cell..

LRRK2 is a biological enzyme switch called a kinase. Many disease-related mutations in the LRRK2 gene produce overactivated forms. This activated enzyme causes the production of pathological LRRK2 filaments in brain cells, causing cell dysfunction and death that disrupt nerve function in patients with Parkinson’s disease.

Other researchers have obtained certain structures from the large LRRK2 protein, but the structure determined by Sun and his colleagues is the first high-resolution structure of the complete molecule.

The researchers used electronic cryomicroscopy (cryo-EM) to determine the LRRK2 structure. This analytical technique cools molecules to ultra-low temperatures and uses an electron beam to image them. By analyzing the patterns in the resulting image, scientists can build the detailed structure of the molecule.

Obtaining the full-length LRRK2 structure is important in designing a targeted drug for Parkinson’s disease, Sun said. Only this structure can reveal how the enzyme is regulated, he said. Other researchers have found molecules containing kinase domains that perform the biochemical switching function of LRRK2. We have decided on some structures. However, the regulation of enzymes such as LRRK2 involves other regions of the molecule, which can alter the overall shape of the protein and activate the kinase domain.

“If you simply design Medication There are around 600 kinases in the human body, and all kinases are so similar that it is difficult to achieve specificity when targeting the kinase domain, ”says Sun. Regulations allow for the specificity of drug design. Therefore, this structure provides a new direction for the design of LRRK2 inhibitors. “

Importantly, the researchers determined not only the structure of a single LRRK2 molecule, called a “monomer,” but also the structure of two linked LRRK2s. molecule, Called “Dimer”. Obtaining the structure of the inactive LRRK2 dimer is important for further study of LRRK2 function, Sun said.

“In the actual physiological state, LRRK2 is only active in the case of dimers,” he said. “Therefore, this dimeric structure is a starting point for putting together the puzzle of how LRRK2 works in cells. Currently, the activity of the LRRK2 dimer makes it possible to study its function. I am working on how to generate a type. “

A high-resolution structural study of full-length LRRK2 by researchers also identified intramolecular “disease hot spots”. These hot spots are areas of LRRK2 where mutations are known to cause disease. Identifying these hot spots provides important structural clues as to how disease-causing mutations abnormally activate LRRK2, Sun said.

Researchers too Construction It is one of the most common variants of LRRK2 called GS2019S, which is known to cause Parkinson’s disease.

“This mutation is an important target for drug discovery, so if the mutant could be specifically inactivated with a drug, there would be a potential cure for this type of disease,” he said.

Sun and his colleagues also used their structural studies to explore a completely different approach to treating Parkinson’s disease. Researchers have found that genetic modification of just one of the molecules connecting two segments of a dimer negates the enzyme’s ability to produce pathological LRRK2 filaments that damage and kill brain cells. I discovered that there is a possibility.

“If we could design a drug that does the same thing, that is, a drug that prevents the pathological formation of these fibers, that could be another way to treat Parkinson’s disease,” Sun said. “This approach is less researched than efforts to prevent mutation-induced gain of function in LRRK2.”


Elucidation of the protein structure of Parkinson’s disease in cells using a novel method


For more information:
Alexander Myasnikov et al, Structural analysis of complete human LRRK2, cell (2021). DOI: 10.1016 / j.cell.2021.05.004
Journal Information:
cell

Quote: Enzyme Structure That Paves the Way for New Drugs for Parkinson’s Disease (2021, June 9) was published on June 9, 2021 at https://medicalxpress.com/news/2021-06-enzyme- parkinson-pathways- Obtained from drugs.html

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Enzyme structure that paves the way for new drugs in Parkinson’s disease

Enzyme structure that paves the way for new drugs in Parkinson’s disease


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