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Related Concept Videos

Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
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Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

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Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
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Allosteric Regulation01:08

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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Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Amyloid Fibrils03:03

Amyloid Fibrils

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Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining,...
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Ligand Binding and Linkage00:49

Ligand Binding and Linkage

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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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Related Experiment Video

Updated: Jun 3, 2025

Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions
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Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions

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Developing Allosteric Chaperones for GBA1-Associated Disorders-An Integrated Computational and Experimental Approach.

Marta Montpeyo1, Natàlia Pérez-Carmona2, Elena Cubero2

  • 1Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08035 Barcelona, Spain.

International Journal of Molecular Sciences
|January 11, 2025
PubMed
Summary
This summary is machine-generated.

Researchers discovered novel compounds that act as pharmacological chaperones for glucocerebrosidase (GCase). Compound 3 shows promise for treating GBA1-related neurological disorders like Parkinson's disease due to its brain penetration.

Keywords:
GBA1Gaucher diseaseParkinson’s diseaseglucocerebrosidaselysosomal storage diseaselysosomepharmacological chaperone

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Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay

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Area of Science:

  • Biochemistry
  • Neuroscience
  • Pharmacology

Background:

  • Mutations in the GBA1 gene impair glucocerebrosidase (GCase) function.
  • GCase deficiency is linked to Gaucher disease and increased Parkinson's disease risk.
  • Developing effective GCase modulators is crucial for these GBA1-related disorders.

Purpose of the Study:

  • To discover and characterize novel allosteric pharmacological chaperones for GCase.
  • To identify compounds that enhance GCase activity and stability in cellular models.
  • To evaluate the therapeutic potential of lead compounds for GBA1-related neurological conditions.

Main Methods:

  • Employed computational approaches including virtual screening and structure-activity relationship optimization.
  • Validated identified compounds using experimental methods in patient-derived cells and neuronal models.
  • Conducted pharmacokinetic studies to assess brain penetration of lead candidates.

Main Results:

  • Identified several novel allosteric pharmacological chaperones for GCase.
  • Compound 3 significantly enhanced GCase activity and protein levels.
  • Compound 3 reduced toxic substrate accumulation in neuronal models and demonstrated favorable brain penetration.

Conclusions:

  • The study presents a successful framework for developing allosteric GCase modulators.
  • Compound 3 is a promising lead candidate for treating GBA1-related disorders, including Parkinson's disease.
  • The blood-brain barrier penetration of compound 3 highlights its potential for CNS-targeted therapies.