Mechanism of Action

Insulin acts as a ligand that binds to the insulin receptor. The insulin receptor is a multi-domain, transmembrane, tyrosine kinase protein embedded in the plasma membrane target cells such as adipocytes, hepatocytes, and skeletal muscles. When insulin binds and activates the receptor, conformational changes occur resulting in a signaling cascade. Part of this signaling cascade involves the translocation of the glucose transporters (GLUT4) to the cell surface where they contribute to glucose uptake. 

Insulin and Insulin receptor mechanism of action 

Insulin Receptor Structure & Domains 

PDB 6PXV Surface 

The insulin receptor is homodimer covalently linked by several disulfide bonds. Its overall shape is symmetrical and resembles a single hole puncher. Up to 4 insulins can bind to the insulin receptor at each site: site 1, 1', 2, and 2'. The insulin receptor contains several domains: two Leu rich domains (L1 and L2), an  α-CT domain, and three fibronectin domains (Fn III-1, -2, and -3).

 

 

 

 

Insulin Binding 

Insulin binding to site 1 and 1' engages the L1 and α-CT domain. The A chain predominantly binds to the α-CT domain while the B chain binds to both the L1 and α-CT domain. Binding at site 2 and 2' involves the FnIII-2 domain and can occur in coordination with binding at site 1 or independently of it. Insulin is bound via hydrogen bonds and Van der Waals interactions. 

PDB 6PXV domains 

 

 

 

     PDB 6PXV Site 1 and Site 2 Interactions

 

 

 

Due the negative cooperativity exhibited when insulin binds to the receptor, there is a significantly large difference in insulin's binding affinity for site 1 and site 2. With a Kd value 10-30nM in site 1 and about 400nM in site 2, Insulin has a much greater affinity for site 1 than site 2. This makes binding at site 2 only observable when 2 to 4 insulins are bound to the insulin receptor which occurs when insulin concentrations are greater than 100nm above physiological conditions. 

 

 PDB 6PXV Site 1 and Site 2 details

 

 

 

 

 

 

 

References 

  1. Choi E, Bai X-C. 2023. The Activation Mechanism of the Insulin Receptor: A Structural Perspective. Annual Review of Biochemistry. 92:247–272. doi:https://doi.org/10.1146/annurev-biochem-052521-033250. [accessed 2023 Sep 11]. https://pubmed.ncbi.nlm.nih.gov/37001136/.

  2. De Meyts P. 2000. The Insulin Receptor and Its Signal Transduction Network. Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, et al., editors. PubMed. https://www.ncbi.nlm.nih.gov/books/NBK378978/#ins-rec-transduct.toc-definition-of-the-receptor-binding-surfaces-on-the-insulin-and-receptor-molecules.

  3. Kaplan SA. 1984. The insulin receptor. The Journal of pediatrics. 104(3):327–36. doi :https://doi.org/10.1016/s0022-3476(84)81090-2. [accessed 2019 Nov 13]. https://www.ncbi.nlm.nih.gov/pubmed/6368773. 
  4. PDB101: Diabetes Mellitus: Diabetes Mellitus: undefined: Insulin Receptor. RCSB: PDB-101. https://pdb101.rcsb.org/global-health/diabetes-mellitus/drugs/insulin/target/insulin-receptor.

  5. Sevlever F, Di Bella JP, Ventura AC. 2020. Discriminating between negative cooperativity and ligand binding to independent sites using pre-equilibrium properties of binding curves. Finley S, editor. PLOS Computational Biology. 16(6):e1007929. doi:https://doi.org/10.1371/journal.pcbi.1007929.

  6. Uchikawa E, Choi E, Shang G, Yu H, Bai X. 2019. Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor–ligand complex. eLife. 8. doi :https://doi.org/10.7554/elife.48630.
  7. Yunn N-O, Kim J, Ryu SH, Cho Y. 2023 Oct 2. A stepwise activation model for the insulin receptor. Experimental & Molecular Medicine.:1–15. doi:https://doi.org/10.1038/s12276-023-01101-1. https://www.nature.com/articles/s12276-023-01101-1#Sec2.

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