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 two states: active and inactive (Figure 2). The exists in dynamic equilibrium where binding favors the active state. In this active state, TSH will bind and keep the active state in the up position because of clashes between bound TSH and the cell membrane.[1].
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.[2].
M22 Agonist
is a
monoclonal antibody that was isolated from a patient with
Graves' Disease. In Graves' disease, autoantibodies mimic TSH function and cause thyroid overactivity.
[2]. The M22
autoantibody activates TSHR by causing a membrane clash with the ECD and 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 because it is a potent activator for TSHR.
[1] Although M22 binds in a similar manner to TSH, M22 does not interact with the hinge region when bound to TSHR, whereas TSH bound to TSHR does.
[1] This finding shows 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.
CS-17 Inverse Agonist
is a monoclonal antibody that acts as an inverse agonist for TSHR constitutive activity. [3]. CS-17 interacts with the ECD of the TSHR protein on the convex side of the LRRD. When bound to TSHR, CS-17 suppresses TSHR function by keeping the receptor in the inactive state (Figure 3). Clash with the cell membrane does not allow the inactive form of TSHR to flip to the active conformation. CS-17 plays a unique role with GPCRs. This type of inhibition is not commonly seen in many biological systems and therefore leads to this method of inhibition being a great target for drug design and future research.[3]. Due to its unique inhibition, CS-17 can be a popular therapy for many thyroid diseases where the thyroid is overactive.
TSH Agonist
This clash is caused by glycosylations of an Asn52 on the . Addition of N-acetyl glucosamine modifications create steric clashes between TSH and the cell membrane, keeping TSHR in the active state.
