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Related Concept Videos

Ligand Binding and Linkage00:49

Ligand Binding and Linkage

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 the...
Ligand Binding Sites02:40

Ligand Binding Sites

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...
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.

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Related Experiment Video

Updated: May 10, 2026

Using Phage Display to Develop Ubiquitin Variant Modulators for E3 Ligases
06:30

Using Phage Display to Develop Ubiquitin Variant Modulators for E3 Ligases

Published on: August 27, 2021

Development of High-Affinity Ligands for Human UBR2.

Shih-Ting Huang1, Abdelfattah Faouzi, Nicole Thomas

  • 1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0021, United States.

Journal of Medicinal Chemistry
|May 8, 2026
PubMed
Summary
This summary is machine-generated.

Researchers developed high-affinity small-molecule ligands targeting UBR2, a protein implicated in cancer and diabetes cachexia. These novel ligands show promise for therapeutic development against cachexia by effectively binding UBR2.

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Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta
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Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta

Published on: December 5, 2019

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Last Updated: May 10, 2026

Using Phage Display to Develop Ubiquitin Variant Modulators for E3 Ligases
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Published on: August 27, 2021

Screening Traditional Chinese Medicine Compounds for Inhibiting UCHL3 Activity Based on Molecular Docking and Deubiquitinating Enzyme Probe Technology
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Screening Traditional Chinese Medicine Compounds for Inhibiting UCHL3 Activity Based on Molecular Docking and Deubiquitinating Enzyme Probe Technology

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Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta
10:27

Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta

Published on: December 5, 2019

Area of Science:

  • Biochemistry
  • Structural Biology
  • Drug Discovery

Background:

  • UBR box-containing E3 ligases target protein N-termini.
  • UBR2 is a therapeutic target for cachexia associated with cancer and diabetes.
  • High-affinity small-molecule ligands for UBR2 are currently lacking.

Purpose of the Study:

  • To develop high-affinity small-molecule ligands for UBR2.
  • To elucidate the molecular mechanisms of UBR2 ligand binding.
  • To evaluate the therapeutic potential of UBR2 ligands in cachexia models.

Main Methods:

  • Peptidomimetic approach incorporating unnatural amino acids.
  • High-resolution cocrystal structural analysis (∼1.2 Å).
  • In vitro binding assays to determine affinity (Kd) and selectivity.
  • In vitro cellular models of cancer-induced cachexia.

Main Results:

  • Developed UBR2 ligands with high affinity (Kd ∼ 20-40 nM).
  • Achieved 10-fold selectivity for UBR2 over its homolog UBR1.
  • Determined high-resolution structures revealing binding mechanisms.
  • Demonstrated attenuation of cancer-induced cachexia in a cellular model.

Conclusions:

  • UBR boxes are druggable targets.
  • High-affinity UBR2 ligands can be developed using peptidomimetics.
  • These findings support targeting UBR E3 ligases for novel cachexia therapeutics.