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Related Concept Videos

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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Ligand Binding and Linkage00:49

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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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Cooperative Allosteric Transitions01:58

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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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Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
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Using a Function-First "Scout Fragment"-Based Approach to Develop Allosteric Covalent Inhibitors of Conformationally

Jared R Ramsey1,2, Patrick M M Shelton2, Tyler K Heiss2

  • 1Tri-Institutional PhD Program in Chemical Biology, New York, New York 10021, United States.

Journal of the American Chemical Society
|December 22, 2023
PubMed
Summary
This summary is machine-generated.

Researchers developed a novel approach using electrophilic scout fragments to create covalent inhibitors for helicases, enzymes crucial in DNA/RNA processes and disease. This method successfully targeted viral and human helicases, offering new therapeutic strategies.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Enzymology
  • Drug Discovery

Background:

  • Helicases are essential ATP-dependent mechanoenzymes that remodel nucleic acids, playing critical roles in DNA/RNA metabolism, translation, and genome maintenance.
  • Dysfunctional helicases are implicated in various diseases, including cancer and viral infections, making them attractive therapeutic targets.
  • Developing specific chemical inhibitors for helicases is challenging due to their high conformational dynamics.

Purpose of the Study:

  • To explore the utility of electrophilic 'scout fragments' for developing covalent inhibitors against helicases.
  • To identify druggable allosteric sites in conformationally dynamic mechanoenzymes.
  • To develop a covalent inhibitor targeting SARS-CoV-2 nsp13 and assess the potential of scout fragments against human helicases.

Main Methods:

  • Employed a function-first strategy combining enzymatic assays with enantiomeric probe pairs and mass spectrometry.
  • Utilized scout fragments, known from chemical proteomic studies, to target helicase allosteric sites.
  • Tested inhibitor efficacy against SARS-CoV-2 nsp13 (Superfamily-1 helicase) and human BLM and WRN helicases (Superfamily-2).

Main Results:

  • Successfully developed a covalent inhibitor that selectively targets an allosteric site in SARS-CoV-2 nsp13.
  • Demonstrated that scout fragments can inhibit the activity of human Superfamily-2 helicases, BLM and WRN.
  • Validated the potential of scout fragments for discovering covalent inhibitor starting points in dynamic enzymes.

Conclusions:

  • Electrophilic scout fragments represent a viable strategy for developing covalent inhibitors against challenging enzyme targets like helicases.
  • The study presents a novel approach for identifying allosteric sites and generating starting points for covalent drug discovery.
  • This methodology holds promise for developing therapeutics against viral pathogens and human diseases associated with helicase dysfunction.