Active and Inactive Form
Figure 2: Inactive form of the thyrotropin receptor shown in blue (PDB: 7T9M). Active form of the thyrotropin receptor shown in green (PDB: 7T9I).
The TSHR protein exists in dynamic equilibrium between two states: active and inactive (Figure 2). will bind and keep the active state in the up position as a result of clashes between bound TSH and the cell membrane.[1]. cause this clash on the .
TSHR Agonists and Antagonists
Chemical agonists are found in many living systems and serve as a way to activate receptors or pathways that are necessary for a wide array of biological processes. Chemical antagonists block or inhibit biological processes. Different types of agonists/antagonists exist within the body including hormones, antibodies, and neurotransmitters. The body naturally produces autoantibodies that can act as agonists and mimic the activating mechanism of the natural hormone leading to disease.[2].
M22 Agonist
is a
monoclonal antibody that is produced by patients with
Graves' Disease. In Graves' disease, autoantibodies mimic TSH function and cause thyroid overactivity.
[2]. Grave's Disease is an autoimmune disease that is a result of hyperthyroidism, where too much TSH is being produced. This disease
effects 1 in 100 Americans and especially women or people older than 30 years of age. The M22
autoantibody activates TSHR by causing a membrane clash with the ECD and the cell membrane, keeping the TSHR in the active state by preventing the TSHR from rotating to the inactive state (Figure 3). M22 mimics TSH activation of TSHR, and is a potent activator for intracellular signaling.
[1] Although M22 binds in a similar manner to TSH, M22 does not interact with the hinge region when bound to TSHR.
[1] These findings show that the hinge region is not necessary for the activation of TSHR, and leads to the discovery of other methods of activation.
Figure 3: Agonist and antagonist drugs for activating or inactivating the TSHR protein. Here the membrane clashes are demonstrated on TSHR with different agonists attached. CS-17 is orange, TSH is purple, and M22 is blue in the figure. The TSHR protein is green and embedded in the protein.
CS-17 Inverse Agonist
is a monoclonal antibody that acts as an inverse agonist for TSHR constitutive activity. [3]. An example of a disease caused by inverse agonists is hypothyroidism. The most common cause of hypothyroidism is Hashimoto’s disease. Without enough TSH to bind TSHR, the pathway remains inactive and thus metabolic processes are inhibited in this pathway. CS-17 interacts with the ECD of the TSHR protein on the
of the LRRD, suppressing TSHR function by keeping the receptor in the inactive state (Figure 3). Clash of bound CS-17 with the cell membrane locks TSHR in the inactive form. This type of inhibition is uncommon and is a promising mechanism for future drug design and research to combat hypothyroidism.[3].
