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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

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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.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
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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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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
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Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
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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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Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome.  Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form...
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Updated: Jul 1, 2025

Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
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Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function.

John L Silberstein1,2, Jasper Du3, Kun-Wei Chan4

  • 1Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305.

Proceedings of the National Academy of Sciences of the United States of America
|March 14, 2024
PubMed
Summary

Lymphocyte activation gene-3 (LAG-3) dimerization via domain 2 is crucial for its inhibitory function. Targeting LAG-3 domains can block ligand binding and offers new immunotherapy strategies.

Keywords:
LAG-3cancer immunotherapydimerizationimmune checkpointstructural biology

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Area of Science:

  • Immunology
  • Structural Biology
  • Cancer Immunotherapy

Background:

  • Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor on T cells and a key immunotherapy target.
  • LAG-3's Domain 1 (D1) was thought to be the primary interaction site with MHCII and FGL1 ligands.

Purpose of the Study:

  • To elucidate the structural basis of LAG-3 function and identify novel therapeutic targets.
  • To investigate the role of LAG-3 dimerization in its inhibitory activity and ligand binding.

Main Methods:

  • High-resolution structural analysis of glycosylated mouse LAG-3 ectodomain.
  • Site-directed mutagenesis to disrupt dimerization interfaces.
  • Biochemical assays to assess ligand binding (MHCII, FGL1) and T cell suppression.

Main Results:

  • LAG-3 undergoes cis-homodimerization through Domain 2 (D2), which is essential for its function.
  • A novel protein-glycan interaction within the dimer interface influences D1 orientation.
  • Mutations disrupting D2 dimerization abolished ligand binding and T cell suppression.
  • Antibodies targeting D1, D2, and D3 domains blocked dimerization and ligand binding, suggesting allosteric regulation.

Conclusions:

  • LAG-3 dimerization, regulated by D2, is critical for its inhibitory function and ligand interactions.
  • Novel epitopes beyond D1 can be targeted for developing LAG-3-based immunotherapies.
  • Understanding LAG-3 structure and dimerization provides new avenues for cancer treatment.