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▎Editor of WuXi AppTec's content team Parkinson's disease (PD) is a common neurodegenerative disease.
At least one out of every 100 people over 60 is sickened
.
Scientists studying the pathogenesis of Parkinson's disease have discovered that mutations in a protease called LRRK2 are one of the key causes of familial and occasional Parkinson's disease
.
This protein has therefore become a potential drug target for the development of Parkinson's disease therapy in recent years
.
Image source: 123RF Recently, the top academic journal Cell published a research paper online.
The team led by Dr.
Sun Ji, a structural biologist at St.
Jude Children's Research Hospital, cracked human LRRK2 for the first time The high-resolution structure of the full-length protein provides mechanistic insights into the physiological and pathological effects of LRRK2
.
This result provides structural insights for the development of new therapies to treat Parkinson's disease, and opens up a research approach that specifically targets abnormal LRRK2 proteins
.
Protease LRRK2 participates in a variety of cellular physiological processes.
As a kinase, it acts like a switch for biological enzymatic reactions
.
A variety of mutations in the gene encoding LRRK2 will produce an over-activated form of kinase, so that pathological LRRK2 protein filaments are formed in brain cells, leading to cell dysfunction and death, thereby destroying neuronal function in patients with Parkinson's disease
.
In view of the importance of LRRK2, some previous studies have already understood part of the domain of LRRK2 protein
.
However, the LRRK2 protein is composed of 7 domains and has a complex composition.
Understanding the complete structure can reveal how this enzyme is regulated, which is essential for the design of drugs for Parkinson's disease
.
In this study, Dr.
Sun Ji and colleagues used cryo-electron microscopy (cryo-EM) technology to crack the high-resolution structure of the complete LRRK2 protein molecule for the first time
.
"There are about 600 kinases in the human body, and all kinases look very similar.
If we only design drugs that target the kinase domain, it is difficult to achieve specificity
.
" Dr.
Sun said, "But if we can understand this protein How to be regulated, can target this regulatory effect, and achieve specificity when designing drugs
.
The
complete protein structure provides a new direction for the design of LRRK2 inhibitors
.
"▲Corresponding author Dr.
Sun Ji (middle) and two The authors Dr.
Hanwen Zhu and Dr.
Patricia Hixson (picture source: Reference [2]) The high-resolution structure of the full-length LRRK2 allows researchers to identify some of the “disease hotspots” in the molecule, and a variety of diseases that are known to cause disease.
Mutations occur in these areas
.
Identifying these hot spots helps to understand why disease-causing mutations activate LRRK2 abnormally
.
One of the most common mutant forms of LRRK2 is called G2019S, which is known to cause Parkinson's disease
.
Researchers can further design drugs to inactivate this mutant by analyzing the structure of this mutant, providing an opportunity to treat Parkinson's disease
.
▲Full-length LRRK2 structure in inactivated state (picture source: Reference [1]) More importantly, the researchers not only determined the structure of a single LRRK2 molecule (ie "monomer"), but also determined two connected LRRK2 The structure of the molecule (ie "dimer") provides a basis for further research on the function of LRRK2
.
"Under real physiological conditions, LRRK2 is only active in its dimer form," Dr.
Sun explained.
"For the mystery of how LRRK2 works in cells, the dimer structure obtained this time will be a puzzle.
The starting point
.
"Using this structure, the researchers also proposed a new treatment for Parkinson's disease
.
Researchers have found that genetic modification of the junction of the two parts of the dimer can prevent LRRK2 from producing pathological filaments
.
"If the drugs we design can also prevent the pathological formation of these filaments, it may be another way to treat Parkinson's disease
.
" Dr.
Sun said
.
Reference [1] Alexander Myasnikov et al.
, (2021) Structural analysis of the full-length human LRRK2.
Cell.
Doi: https://doi.
org/10.
1016/j.
cell.
2021.
05.
004[2] Structure of enzyme that causes Parkinson's promises pathways to new drugs.
Retrieved June 9, 2021 from https:// causes-parkinsons-promises-pathways-to-new-drugs.
html
At least one out of every 100 people over 60 is sickened
.
Scientists studying the pathogenesis of Parkinson's disease have discovered that mutations in a protease called LRRK2 are one of the key causes of familial and occasional Parkinson's disease
.
This protein has therefore become a potential drug target for the development of Parkinson's disease therapy in recent years
.
Image source: 123RF Recently, the top academic journal Cell published a research paper online.
The team led by Dr.
Sun Ji, a structural biologist at St.
Jude Children's Research Hospital, cracked human LRRK2 for the first time The high-resolution structure of the full-length protein provides mechanistic insights into the physiological and pathological effects of LRRK2
.
This result provides structural insights for the development of new therapies to treat Parkinson's disease, and opens up a research approach that specifically targets abnormal LRRK2 proteins
.
Protease LRRK2 participates in a variety of cellular physiological processes.
As a kinase, it acts like a switch for biological enzymatic reactions
.
A variety of mutations in the gene encoding LRRK2 will produce an over-activated form of kinase, so that pathological LRRK2 protein filaments are formed in brain cells, leading to cell dysfunction and death, thereby destroying neuronal function in patients with Parkinson's disease
.
In view of the importance of LRRK2, some previous studies have already understood part of the domain of LRRK2 protein
.
However, the LRRK2 protein is composed of 7 domains and has a complex composition.
Understanding the complete structure can reveal how this enzyme is regulated, which is essential for the design of drugs for Parkinson's disease
.
In this study, Dr.
Sun Ji and colleagues used cryo-electron microscopy (cryo-EM) technology to crack the high-resolution structure of the complete LRRK2 protein molecule for the first time
.
"There are about 600 kinases in the human body, and all kinases look very similar.
If we only design drugs that target the kinase domain, it is difficult to achieve specificity
.
" Dr.
Sun said, "But if we can understand this protein How to be regulated, can target this regulatory effect, and achieve specificity when designing drugs
.
The
complete protein structure provides a new direction for the design of LRRK2 inhibitors
.
"▲Corresponding author Dr.
Sun Ji (middle) and two The authors Dr.
Hanwen Zhu and Dr.
Patricia Hixson (picture source: Reference [2]) The high-resolution structure of the full-length LRRK2 allows researchers to identify some of the “disease hotspots” in the molecule, and a variety of diseases that are known to cause disease.
Mutations occur in these areas
.
Identifying these hot spots helps to understand why disease-causing mutations activate LRRK2 abnormally
.
One of the most common mutant forms of LRRK2 is called G2019S, which is known to cause Parkinson's disease
.
Researchers can further design drugs to inactivate this mutant by analyzing the structure of this mutant, providing an opportunity to treat Parkinson's disease
.
▲Full-length LRRK2 structure in inactivated state (picture source: Reference [1]) More importantly, the researchers not only determined the structure of a single LRRK2 molecule (ie "monomer"), but also determined two connected LRRK2 The structure of the molecule (ie "dimer") provides a basis for further research on the function of LRRK2
.
"Under real physiological conditions, LRRK2 is only active in its dimer form," Dr.
Sun explained.
"For the mystery of how LRRK2 works in cells, the dimer structure obtained this time will be a puzzle.
The starting point
.
"Using this structure, the researchers also proposed a new treatment for Parkinson's disease
.
Researchers have found that genetic modification of the junction of the two parts of the dimer can prevent LRRK2 from producing pathological filaments
.
"If the drugs we design can also prevent the pathological formation of these filaments, it may be another way to treat Parkinson's disease
.
" Dr.
Sun said
.
Reference [1] Alexander Myasnikov et al.
, (2021) Structural analysis of the full-length human LRRK2.
Cell.
Doi: https://doi.
org/10.
1016/j.
cell.
2021.
05.
004[2] Structure of enzyme that causes Parkinson's promises pathways to new drugs.
Retrieved June 9, 2021 from https:// causes-parkinsons-promises-pathways-to-new-drugs.
html
