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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 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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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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Conserved Binding Sites01:49

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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
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Optimal allosteric stabilization sites using contact stabilization analysis.

Alex Dickson1, Christopher T Bailey2, John Karanicolas3

  • 1Department of Biochemistry & Molecular Biology and the Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, Michigan, 48824.

Journal of Computational Chemistry
|October 25, 2016
PubMed
Summary
This summary is machine-generated.

Understanding protein stabilization is key to restoring enzyme function. This study develops a framework to predict effective allosteric binding sites and disulfide bond locations for enhancing protein stability, crucial for drug design and biotechnology.

Keywords:
allosterychemical rescuecoarse-grained modelmolecular dynamicsprotein re-activationprotein stabilization

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Area of Science:

  • Biophysics
  • Structural Biology
  • Computational Biology

Background:

  • Proteins are susceptible to destabilization by environmental factors like temperature, pH, and mutations.
  • Restoring protein function via stabilizers or disulfide bonds is powerful but lacks understanding of underlying physical principles.
  • Identifying optimal binding sites or disulfide bond locations for active site stabilization remains a challenge.

Purpose of the Study:

  • To present a general framework for predicting allosteric binding sites that correlate with active site stability.
  • To investigate the physical principles governing protein stabilization by analyzing intramolecular contacts.
  • To evaluate the framework's applicability to a destabilized enzyme mutant.

Main Methods:

  • Utilized the Karanicolas-Brooks Gō-like model to simulate enzyme dynamics.
  • Employed Umbrella Sampling to comprehensively explore the conformational landscape of β-glucuronidase.
  • Quantified the correlation between intramolecular contacts and active site stability using a 'stabilization factor'.

Main Results:

  • Developed a method to assign stabilization factors to intramolecular contacts based on their correlation with active site structural changes.
  • Analyzed the impact of different intramolecular contact scaling strengths on stabilization factor calculations.
  • Observed local changes in stabilization factors for a destabilized β-glucuronidase mutant, validating the model.
  • Found that proximity to the active site alone does not determine a contact's ability to confer stability.

Conclusions:

  • The developed framework provides a method for predicting stabilizing interactions in proteins.
  • The study highlights that proximity is insufficient for identifying effective stabilization sites.
  • Findings contribute to understanding protein dynamics and designing strategies for protein stabilization.