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A High-Throughput Enzyme-Coupled Activity Assay to Probe Small Molecule Interaction with the dNTPase SAMHD1
Published on: April 16, 2021
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Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules
Yun Shi1, Philip S Kerry2, Jeffrey D Nanson3
1Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia.
Molecular Cell
|March 25, 2022
Summary
A sterile alpha and TIR motif containing 1 (SARM1) inhibitor transforms into a potent form (1AD) via interaction with nicotinamide adenine dinucleotide (NAD+). Structural insights reveal SARM1 activation mechanisms, crucial for neurodegenerative disease therapeutics.
Area of Science:
- Neuroscience
- Molecular Biology
- Structural Biology
Background:
- Sterile alpha and TIR motif containing 1 (SARM1) is a critical enzyme in axon degeneration.
- SARM1 is a promising therapeutic target for neurodegenerative diseases.
Purpose of the Study:
- To elucidate the structural mechanisms of SARM1 activation and substrate binding.
- To understand how SARM1 inhibitors interact with the enzyme.
- To provide a basis for designing novel SARM1-targeting therapeutics.
Main Methods:
- X-ray crystallography to determine the structures of SARM1 in complex with inhibitors and activators.
- Biochemical assays to study enzyme activity and inhibitor interactions.
Main Results:
- A SARM1 inhibitor undergoes base exchange with nicotinamide adenine dinucleotide (NAD+) to form a bona fide inhibitor, 1AD.
- Nicotinamide mononucleotide (NMN) binding induces conformational changes, reorienting armadillo repeat (ARM) domains and disrupting ARM:TIR interactions.
- Active SARM1 forms a two-stranded TIR domain assembly where the active site spans two molecules, explaining the necessity of self-association for NADase activity.
Conclusions:
- Structural data reveals the molecular mechanisms underlying SARM1 activation and NAD+ binding.
- Understanding these mechanisms facilitates the rational design of new therapeutic strategies for neurodegenerative conditions by targeting SARM1.
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