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Related Concept Videos

Conserved Binding Sites01:49

Conserved Binding Sites

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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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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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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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Protein-Drug Binding: Mechanism and Kinetics01:16

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Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
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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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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.
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Updated: Oct 1, 2025

Identification of Small Molecule-binding Proteins in a Native Cellular Environment by Live-cell Photoaffinity Labeling
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Identification of Small Molecule-binding Proteins in a Native Cellular Environment by Live-cell Photoaffinity Labeling

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How does a small molecule bind at a cryptic binding site?

Yibing Shan1, Venkatesh P Mysore1, Abba E Leffler1

  • 1D. E. Shaw Research, New York, New York, United States of America.

Plos Computational Biology
|March 3, 2022
PubMed
Summary
This summary is machine-generated.

Researchers used molecular dynamics simulations to study how small molecules bind to cryptic sites in protein-protein interactions (PPIs), aiding drug discovery for diseases.

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Area of Science:

  • Biochemistry and Structural Biology
  • Computational Drug Discovery

Background:

  • Protein-protein interactions (PPIs) are crucial for cellular functions and represent promising drug targets.
  • Designing drugs to inhibit PPIs is challenging due to cryptic binding sites that only form upon ligand interaction.

Purpose of the Study:

  • To understand how small molecules bind to cryptic sites at protein-protein interaction interfaces.
  • To evaluate the utility of molecular dynamics (MD) simulations and free energy perturbation (FEP) for drug design targeting PPIs.

Main Methods:

  • Conducted unbiased, all-atom MD simulations of small-molecule inhibitors binding to interleukin 2 (IL2).
  • Utilized free energy perturbation (FEP) calculations to analyze binding poses and distinguish native from non-native interactions.

Main Results:

  • MD simulations revealed stable binding poses of small molecules at the IL2 PPI interface, forming a defined binding site.
  • The bound small molecule stabilized the IL2 binding groove, which is transiently formed when unbound.
  • FEP calculations successfully differentiated between correct and incorrect binding poses identified in simulations.

Conclusions:

  • MD simulations combined with FEP can effectively identify cryptic binding sites at PPI interfaces.
  • This approach offers a promising strategy for the rational design of small molecules to inhibit disease-related PPIs.