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Related Concept Videos

Allosteric Proteins-ATCase01:19

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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 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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Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
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Related Experiment Video

Updated: Jun 21, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Multiple Functional Protein-Protein Interaction Interfaces Allosterically Regulate ATP-Binding in Cyclin-Dependent

Krishna Kant Vishwakarma1, Ullas Seetharam Kolthur2,3, Ravindra Venkatramani1

  • 1Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, India.

Proteins
|July 16, 2024
PubMed
Summary
This summary is machine-generated.

Acetylation of cyclin-dependent kinase 1 (CDK1) affects ATP binding and protein interactions. Molecular dynamics simulations reveal allosteric regulation between the CDK1 active site and its protein-protein interaction interfaces.

Keywords:
ATP bindingallosterycyclin‐dependent kinase 1dynamicsentropymolecular dynamics simulationprotein–protein interactions

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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Cyclin-dependent kinase 1 (CDK1) is crucial for cell cycle progression.
  • CDK1 activity is regulated by interactions with Cyclin-B, substrate, and Cks proteins.
  • Active site acetylation of CDK1 impacts Cyclin-B binding, suggesting long-range communication.

Purpose of the Study:

  • To demonstrate an allosteric link between the CDK1 active site and its protein-protein interaction (PPI) interfaces.
  • To investigate the effect of acetylation on ATP binding to CDK1.
  • To elucidate the mechanisms of long-range communication within CDK1.

Main Methods:

  • Atomistic molecular dynamics (MD) simulations were employed.
  • ATP binding free energies were calculated for native (K33wt) and modified CDK1 forms (K33Ac, K33Q, K33R).
  • Free energy decomposition and statistical analysis were used to assess entropic responses and correlations.

Main Results:

  • ATP binding is strongest in the native K33wt CDK1 compared to modified forms.
  • Nonlocal entropic responses were observed in the α-helix, activation loop (A-loop), and β-β H segments upon ATP binding/perturbation.
  • These segments mediate interactions with Cyclin-B, substrate, and Cks proteins, respectively.
  • Correlation between entropic responses and dynamical changes was lost in a significant portion of the dataset.

Conclusions:

  • A general allosteric link exists between the CDK1 active site and its three major PPI interfaces.
  • This study uncovers a novel mode of ATP binding regulation mediated by multiple PPI interfaces in CDK1.
  • Bidirectional communication between the active site and the CDK1:Cyclin-B interface is confirmed.