Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

Insulin: The Receptor and Signaling Pathways01:28

Insulin: The Receptor and Signaling Pathways

2.8K
Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but...
2.8K
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

841
Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
841
Spare Receptors01:30

Spare Receptors

4.5K
Some receptors remain unoccupied even when an agonist produces a maximal response. Such empty ones are called spare receptors. In presence of spare receptors the maximum effect of an agonist drug is achieved with fewer than 100% of the receptors being occupied. To determine the presence of spare receptors, scientists often compare the concentration of the drug needed to produce 50% of the maximum effect (EC50) with the concentration of the drug needed to occupy 50% of the receptors (Kd). If the...
4.5K
Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

4.0K
Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous...
4.0K
Insulin: Biosynthesis, Chemistry, and Preparation01:25

Insulin: Biosynthesis, Chemistry, and Preparation

1.2K
The endoplasmic reticulum (ER) of pancreatic β-cells synthesizes preproinsulin, which consists of a signal peptide, A and B chains, and a C-peptide. Preproinsulin is then cleaved and folded into proinsulin, which translocates to the Golgi apparatus for sorting and packaging into secretory granules. In these granules, enzymatic clipping generates insulin and C-peptide.
Damage or functional impairment of β-cells inhibits insulin production, leading to diabetes. Diabetes treatment...
1.2K
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

3.9K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
3.9K

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Controlling metal-carbonate phase, form, and function through de novo protein design.

bioRxiv : the preprint server for biology·2026
Same author

Systems-Scale Structural Modeling Reveals the Germline Architecture of Immunodominance.

bioRxiv : the preprint server for biology·2026
Same author

Generative design of programmable asymmetric β-barrel nanopores.

bioRxiv : the preprint server for biology·2026
Same author

De novo design of miniproteins targeting GPCRs.

Nature·2026
Same author

Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance.

bioRxiv : the preprint server for biology·2026
Same author

De novo design of a macrocycle-induced dimerization system for cellular control.

Nature communications·2026

Related Experiment Video

Updated: Jan 15, 2026

An In Ovo Model for Testing Insulin-mimetic Compounds
06:09

An In Ovo Model for Testing Insulin-mimetic Compounds

Published on: April 23, 2018

11.1K

Tuning insulin receptor signaling using de novo-designed agonists.

Xinru Wang1, Sarah Cardoso2, Kai Cai3

  • 1Department of Biochemistry, University of Washington, Seattle, WA, USA; Institute for Protein Design, University of Washington, Seattle, WA, USA.

Molecular Cell
|October 14, 2025
PubMed
Summary
This summary is machine-generated.

Scientists designed synthetic insulin receptor (IR) agonists that trigger distinct cellular responses. These novel agonists show improved glucose lowering and avoid cancer cell proliferation, offering potential therapeutic benefits for metabolic diseases.

Keywords:
cancercomputational protein designdiabetesinsulininsulin receptormetabolismreceptor tyrosine kinasesevere insulin-resistance syndromessignalingtrafficking

More Related Videos

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
10:58

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

Published on: July 25, 2013

17.6K
Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion
07:30

Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion

Published on: May 10, 2018

9.7K

Related Experiment Videos

Last Updated: Jan 15, 2026

An In Ovo Model for Testing Insulin-mimetic Compounds
06:09

An In Ovo Model for Testing Insulin-mimetic Compounds

Published on: April 23, 2018

11.1K
Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
10:58

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

Published on: July 25, 2013

17.6K
Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion
07:30

Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion

Published on: May 10, 2018

9.7K

Area of Science:

  • Biochemistry and Molecular Biology
  • Pharmacology
  • Protein Engineering

Background:

  • Insulin binding to the insulin receptor (IR) triggers conformational changes, activating downstream signaling pathways like AKT and MAPK, which regulate crucial cellular processes such as metabolism and proliferation.
  • Understanding the precise relationship between IR conformational dynamics and downstream signaling is key to developing targeted therapeutics.

Purpose of the Study:

  • To engineer novel synthetic agonists that induce specific conformational changes in the insulin receptor (IR).
  • To investigate how different IR conformational states translate into distinct downstream signaling outcomes.
  • To develop potential therapeutic agents for metabolic and proliferative diseases with improved efficacy and safety profiles compared to insulin.

Main Methods:

  • Utilized de novo protein design to create binders targeting individual extracellular domains of the insulin receptor.
  • Constructed synthetic IR agonists by fusing these binders in various orientations and with differing conformational flexibility.
  • Assessed receptor autophosphorylation, MAPK pathway activation, receptor trafficking, and cell proliferation in response to the synthetic agonists.
  • Evaluated in vivo glucose-lowering effects and activity on disease-associated IR mutants.

Main Results:

  • Generated a series of synthetic IR agonists capable of eliciting a broad spectrum of downstream responses.
  • Identified agonists demonstrating superior potency to insulin, achieving prolonged glucose lowering in vivo.
  • Observed retained activity on insulin receptor mutants linked to disease.
  • Demonstrated that certain synthetic agonists largely avoid the cancer cell proliferation typically induced by insulin.

Conclusions:

  • The study elucidates the intricate link between insulin receptor conformation, dynamics, and downstream signaling.
  • Designed synthetic agonists offer a promising avenue for therapeutic intervention in metabolic and proliferative disorders.
  • These novel agonists present a potentially safer alternative to insulin, with improved efficacy and reduced side effects like cancer cell proliferation.