Allosteric Modulation of Intact γ-Secretase Structural Dynamics

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Gamma-secretase cleaves amyloid precursor proteins, forming amyloid-beta fibrils linked to Alzheimer's disease.
• Gamma-secretase comprises four subunits, including nicastrin (NCT) and presenilin-1 (PS1), crucial for substrate binding and catalytic activity.
• The precise mechanisms coupling substrate binding to catalytic activity in gamma-secretase are not fully understood.

Purpose of the Study:

• To investigate the structural dynamics of human gamma-secretase using computational modeling.
• To elucidate the molecular mechanisms governing substrate access and catalytic activity.
• To identify potential druggable sites for therapeutic intervention.

Main Methods:

• Membrane-coupled anisotropic network modeling of gamma-secretase structure.
• Analysis of nicastrin (NCT) motions relative to presenilin-1 (PS1).
• Druggability simulations to identify inhibition hot spots.

Main Results:

• Identified two types of NCT motions (bending and twisting) influencing the enzyme's 'open' and 'closed' states.
• Revealed an alternating access mechanism for substrate entry and fluctuations in the PS1 central cavity volume.
• Druggability simulations identified hot spots for orthosteric and allosteric inhibition, including a novel allosteric targeting site at the EC/TM domain interface.

Conclusions:

• NCT motions and PS1 cavity fluctuations regulate substrate access and catalytic activity in gamma-secretase.
• The identified allosteric site offers a new strategy for designing gamma-secretase modulators.
• These findings provide a structural basis for developing novel therapeutics against Alzheimer's disease.