Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1‐Mediated Proteolysis of CENP‐A
Cdh1
Indoles
CENP‐A regulation
Science
Q
Spindle Apparatus
Cadherins
Crystallography, X-Ray
Microtubules
Cdh1 Proteins
Structure-Activity Relationship
target identification
Antigens, CD
Proteolysis
colchicine‐binding site inhibitor
Humans
indole terpenoid
Centromere Protein A
Research Article
DOI:
10.1002/advs.202305593
Publication Date:
2024-06-14T09:49:05Z
AUTHORS (18)
ABSTRACT
AbstractCentromere protein A (CENP‐A), a centromere‐specific histone H3 variant, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure‐activity relationship (SAR) study of the cell‐cycle‐arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)‐6‐Br‐JP18 and (+)‐6‐Cl‐JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X‐ray crystallography analysis reveals that both molecules bind to the colchicine‐binding site of β‐tubulin. Treatment of human cells with microtubule‐targeting agents (MTAs), including these two compounds, results in CENP‐A accumulation by destabilizing Cdh1, a co‐activator of the anaphase‐promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP‐A accumulation using small‐molecule tools and highlights the role of Cdh1 in CENP‐A proteolysis.
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CITATIONS (3)
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