The insulin receptor is member of a large family of cell surface receptors with intrinsic protein tyrosine kinase (PTK) activity. The receptor catalyzes the transfer of the gamma phosphate of ATP to selected tyrosine residues of protein substrates. The PTK's play critical roles in cellular proliferation, differentation and metabolism.1 The crystal structure of the unphosphorylated, low activity form of the tyrosine kinase domain of the insulin receptor (IRK) has been known for a while, but in 1997, Stephen Hubbard determined the structure of the tris-phosphorylated, activated form of IRK (IRK3P).2

Insulin is a small polypeptide hormone which is produced in the pancreas by the Islets of Lang.sInsulin is composed of 51 amino acid residues which make up two chains; an A chain of 21 amino acids and a B chain of 30 amino acids. Two disulphide bridges link the two chains and an intrachain disulphide bridge is also found in the A chain.3  Insulin is used in the body to control the usage of glucose and to regulate metabolism.  Diabetes is a disease that results if the body does not produce enough insulin or if the body does not metabolize glucose properly. 

Insulin binds to the tyrosine kinase receptor, located on the cell membranes of the target cells on skeletal muscle tissue, fat tissue, and liver.  The receptors comprise about 0.01 percent of the total membrane.4   The binding of the insulin to the kinase receptor causes the receptor to change confirmation and move into the cell facilitating the entrance of glucose.

Backbone chain




The insulin receptor can also be seen surrounded by a solvent.

Solvent accessible surface area

The insulin receptor, alpha-2, beta-2 protein,  has a tyrosine kinase and a signalling domain in the cytoplasmic region.  The insulin receptor has 2 domains: alpha beta domain and primarily alpha domain. The alpha sub unit contains the insulin binding site. 

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Figure 1Active site on insulin receptor tyrosine kinase (purple)

Beta sheets

The alpha helix structures in the complex are stabilized by hydrogen bonding within the helices.

Alpha helices

Hydrogen bonding

Hydrogen bonding off

In the extracellular region, the insulin receptor has a ligand binding region where it can bind insulin. The insulin does not enter the cell, but the binding of insulin to the receptor sends a signal into the cell relaying information on the concentration of insulin in the blood stream.4 The binding of  insulin to the extracellualr domain (A chains) of the insulin receptor causes the autophosphorylation of the beta unit on the three tyrosine residues, Tyr 1158, Tyr 1162, and Tyr 1163 (B chains) (Figure 2).5   The autophosphorylation causes the activation loop to undergo a major conformational change and enables the kinase to phosphorylate other proteins at the cost of ATP. The primary targets are the insulin receptor substrate proteins (IRS), the phosphorylation of which stimulates a cascade effect that releases enzymes that assist in the regulation of the phosphorylation of the targets of  insulin.2  e kinase

A complex of the insulin receptor and peptide substrate was crystallized and X-ray diffraction was done at a resolution of 1.90A to determine the structure of the complex.  The structure of the complex can be seen below as the insulin receptor (306 residues), which is colored grey and the peptide substrate (18 residues), which is colored pink (Figure 2).2 domain
insulin receptortated view spacefll viewsoad insulin

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Figure 2.2  Comparison of the activation loop conformations of IRK and IRK3P. The activation loop is colored green and contains phosphotyrosines pY1158, pY1162 and pY1163, the catalytic loop is orange and contains the putative catalytic base, D1132.  Also shown are the bound ATP analog (AMP-PNP) and the peptide substrate, pink, containing the acceptor tyrosine, Y(P). The rest of the protein in each case is represented by a semi-transparent molecular surface. Carbon atoms are colored white, nitrogen atoms blue, oxygen atoms red, and phosphorus atoms are yellow.           

Insulin receptor complexed with peptide substrate

Insulin receptor complexed with peptide substrate - Spacefill

Cartoon protein

With spacefill ligand (the orange is peptide substrates and the ATP analog is blue)

The binding of insulin to the insulin receptor causes conformational changes and autophosphorylation.  The phosphorylated insulin receptor tyrosine kinase is more stable than the unphosphorylated protein.  For example, the phosphorylated Tyr 1163 helps stabilize the activation loop by hydrogen bonding to the side chain of Arg 1155 and to the backbone amide nitrogen of Gly 1166.  The phosphorylated insulin receptor has two hydrophobic pockets where the peptide substrate can fit into.5

Hydrophobic areas

The phosphorylation site in insulin receptor substrate 1 (IRS-1) contains the sequence motif Tyr-Met-Xaa-Met (Xaa is any amino acid, Asn in this case). The peptide substrate binds as an anti-parallel beta strand to the end of the activation loop (Figure 3).2 The backbone-backbone interactions between the peptide substrate and the activation loop ensure that the longer tyrosine side chain is selected for phosphorylation rather than a serine/threonine side chain. The methionine residues of the Tyr-Met-Xaa-Met motif bind in two adjacent hydrophobic pockets on the surface of the C-terminal lobe of the kinase.2 

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Figure 3.2 A peptide substrate binding to a tri-phosphorylated insulin receptor, IRK3P. Oxygen atoms are red, nitrogen atoms are blue, carbon atoms of IRK3P are yellow, carbon atoms of the peptide are green, sulfur atoms of IRK3P are green, and sulfur atoms of the peptide are black. Selected hydrogen bonds are shown as white lines, and the red sphere represents a water molecule.

The dot surface command allows a person to see the overall shape and volume of the complex.

Dot surface

Dot surface off


For each receptor, there are two alpha and two beta sub units, all linked together with disulfide bonds which stabilize the insulin receptor, tyrosine kinase. The complex contains 22 disulfide bonds, two of which are made to the peptide substrate.  The other 20 disulfide bonds help hold insulin together.6 

Disulfide bonds (The disulfide bonds are colored yellow)

The charged areas of the protein indicates the basicity/acidity of the residues.

Charged areas (acidic=red, basic=blue, neutral=yellow)

Charged areas (acidic=red, basic=blue, neutral=yellow)- Spacefill

Spin off

Chen Hongying, Guo Chen Yan, and Mikhail L Gishizky have researched the structural characteristics that contribute to the apoptic function of the insulin receptor.  They have discovered that the COOH-terminal 94 amino acids, Phe-1264, and His-1265 are key factors in the death of the receptor.7

Electrostatic surface






5.   Hubbard, Stevan R.  Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog.  Department of Pharmacology and Skirball Institute of Biomolecular        Medicine, New York University Medical Center, New York, NY 10016, USA,  1997.