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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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Related Experiment Video

Updated: Mar 15, 2026

Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation

Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation

Published on: October 4, 2024

A substrate-driven allosteric switch that enhances PDI catalytic activity.

Roelof H Bekendam¹, Pavan K Bendapudi¹, Lin Lin¹

¹Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

Nature Communications

|August 31, 2016

Summary

This summary is machine-generated.

New compounds called bepristats block substrate binding in protein disulfide isomerase (PDI). This inhibition paradoxically boosts PDI’s catalytic activity, impacting platelet aggregation and thrombus formation.

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Area of Science:

Biochemistry
Molecular Biology
Pharmacology

Background:

Protein disulfide isomerase (PDI) is a crucial oxidoreductase in the endoplasmic reticulum, essential for proper protein folding.
PDI comprises distinct domains (a-b-b'-x-a') with specific functions: a/a' domains for disulfide bond shuffling and b/b' domains for substrate binding.
The x-linker connects the b' and a' domains, playing a role in PDI's allosteric regulation.

Purpose of the Study:

To identify novel compounds targeting the substrate-binding pocket of PDI's b' domain.
To investigate the effects of these compounds on PDI's enzymatic activity and function.
To elucidate the allosteric mechanism by which substrate binding influences PDI's catalytic domains.

Main Methods:

Identification and characterization of bepristat compounds.
In vitro assays to assess substrate binding inhibition and catalytic activity.
In vivo studies to evaluate the impact on platelet aggregation and thrombus formation.

Main Results:

Bepristats were identified as reversible inhibitors of substrate binding to the PDI b' domain.
Bepristat binding paradoxically enhanced the catalytic activity of PDI's a and a' domains.
This enhancement was attributed to the displacement of the x-linker, acting as an allosteric switch.
Inhibition of platelet aggregation and thrombus formation in vivo was observed.

Conclusions:

Bepristats represent a novel class of inhibitors targeting PDI's substrate-binding pocket.
A substrate-driven allosteric mechanism enhances catalytic activity in thiol isomerases.
This mechanism, involving x-linker displacement, has implications for understanding PDI function and developing new therapeutics.