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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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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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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis

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Allosteric inhibition explained through conformational ensembles sampling distinct "mixed" states.

Jung Ah Byun1, Bryan VanSchouwen2, Madoka Akimoto2

  • 1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.

Computational and Structural Biotechnology Journal
|December 18, 2020
PubMed
Summary

Allosteric partial agonists for cyclic nucleotide-activated enzymes like PKA, PKG, and EPAC function by stabilizing distinct "mixed" conformational states. This mechanism explains partial agonism and aids in designing potent, selective allosteric inhibitors.

Keywords:
AgonismAllosteric pluripotencyAllosteryAntagonismEPACPKAPKGcAMPcGMP

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Area of Science:

  • Biochemistry and Molecular Pharmacology
  • Enzyme Kinetics and Allosteric Regulation

Background:

  • Allosteric modulation is a key strategy for developing selective and potent enzyme inhibitors.
  • Cyclic nucleotide-activated signaling enzymes, including cAMP-dependent protein kinase (PKA), cGMP-dependent protein kinase (PKG), and exchange protein activated by cAMP (EPAC), are crucial drug targets.

Purpose of the Study:

  • To summarize and critically analyze recent advancements in the mechanisms of allosteric partial agonists targeting PKA, PKG, and EPAC.
  • To elucidate the role of distinct "mixed" conformational states in mediating partial agonism and allosteric pluripotency.
  • To demonstrate how Nuclear Magnetic Resonance (NMR), Molecular Dynamics (MD) simulations, and Ensemble Allosteric Modeling (EAM) can map free-energy landscapes of these conformational ensembles.

Main Methods:

  • Comparative analysis of allosteric partial agonism across PKA, PKG, and EPAC.
  • Integration of Nuclear Magnetic Resonance (NMR) spectroscopy.
  • Application of Molecular Dynamics (MD) simulations and Ensemble Allosteric Modeling (EAM).

Main Results:

  • A common theme of "mixed" conformational state sampling was identified in PKA, PKG, and EPAC partial agonism.
  • These "mixed" states are crucial for explaining partial agonism and allosteric pluripotency, optimizing inhibition while minimizing potency loss.
  • NMR, MD simulations, and EAM were combined to successfully map the free-energy landscape of conformational ensembles containing these "mixed" states.

Conclusions:

  • The study reveals that distinct "mixed" conformational states are central to the mechanism of allosteric partial agonism in cyclic nucleotide-activated enzymes.
  • NMR- and MD-based EAMs provide a quantitative link between protein dynamics and function.
  • These integrated approaches are expected to guide the design of next-generation selective allosteric inhibitors and inform multidrug combination strategies.