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Related Concept Videos

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Allosteric Regulation

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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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Allosteric Modulation of Intact γ-Secretase Structural Dynamics.

Ji Young Lee1, Zhiwei Feng2, Xiang-Qun Xie2

  • 1Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; NIH Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania.

Biophysical Journal
|December 21, 2017
PubMed
Summary

Gamma-secretase, a target for Alzheimer's disease therapeutics, undergoes NCT motions influencing substrate access and catalytic activity. New allosteric inhibition strategies are proposed based on its structure.

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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.