Structure and Molecular Basis for Inhibiting Human SOD1 Aggregation by a Promising Decan Derivative Modulator: A...

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Misfolding and aggregation of human superoxide dismutase (hSOD1) are key features of amyotrophic lateral sclerosis (ALS).
• hSOD1 stability relies on Cu/Zn ions and a disulfide bond; mutations disrupt this, causing aggregation and disease.
• Demetalation and mutations in hSOD1 lead to protein oligomerization, a critical step in ALS pathogenesis.

Purpose of the Study:

• To identify modulators that stabilize hSOD1 structure and inhibit its aggregation.
• To investigate the binding site and affinity of potential inhibitors for hSOD1.
• To explore therapeutic strategies targeting hSOD1's role in ALS.

Main Methods:

• X-ray crystallography to determine the structure of hSOD1 complexed with 1,2,10-decanetriol.
• Biochemical assays to measure binding affinity (e.g., surface plasmon resonance).
• In vitro experiments to assess the inhibition of protein aggregation.

Main Results:

• 1,2,10-decanetriol binds to electrostatic loop and dimer interface regions of hSOD1.
• The crystal structure reveals stabilization of loop regions and the hSOD1 dimeric structure.
• The compound exhibits low nanomolar binding affinity (32.40 ± 0.65 nM) and significantly inhibits hSOD1 aggregation.

Conclusions:

• 1,2,10-decanetriol is the first identified molecule to bind the electrostatic loop of hSOD1, stabilizing its structure.
• This compound effectively inhibits aggregation in various hSOD1 forms, including wild-type and mutants.
• 1,2,10-decanetriol represents a promising scaffold for developing new ALS therapies targeting hSOD1 aggregation.