| Version | 1.0 |
| File Size | 2100 kb |
| File Count | 1 |
| Create Date | August 20, 2022 |
| Update Date | August 20, 2022 |
| Telegram | Join Now |
Summary of Infectious Disease :-
| Version | 1.0 |
| File Size | 5200 kb |
| File Count | 1 |
| Create Date | August 20, 2022 |
| Update Date | August 20, 2022 |
| Telegram | Join Now |
Summary of Hormone Antagonist :-
Pegvisomant is the only member of a new class of drugs that was especially designed to block the GH receptor (GHR) and, therefore, GH action. In this review we will describe the structure and function of GH and its receptor with specific relevance to the discovery and development of GHR antagonists. With respect to clinical applications, we will first discuss the role of Pegvisomant in the treatment of acromegaly. Thereafter, the potential role that Pegvisomant might play in the treatment and prevention of late complications of diabetes mellitus and cancer will be discussed and compared with those of somatostatin analogs in these settings.Rationale for GHR antagonists
GH is secreted by the somatotrophs of the anterior pituitary gland and acts on various tissues to promote growth and influence metabolism. GH signal transduction begins with GH binding to a GHR on the plasma membrane. The cocrystal structure of the GH-GHR complex indicates that GH interacts with a preformed GHR dimer. This interaction is critical for GH-induced intracellular signal transduction. GH has two distinct domains (sites 1 and 2) that bind to the two identical GHRs at the cell surface. After initial, high affinity binding at site I, subsequent binding at site 2 produces functional receptor dimerization. After the GH/GHR interaction, a series of intracellular signaling systems are mobilized, ultimately resulting in the activation or inactivation of genes that are responsible for GH phenotypic effects. In humans and most mammals, the extracellular part of the GHR can be released from the cell surface by proteolytic cleavage, resulting in the generation of a serum GH-binding protein.
Structure of GH
GH is a protein that contains 191 amino acids with two disulfide bonds and four α-helixes. Its molecular mass is approximately 22,000 Da. The structure of GH has been determined by x-ray crystallography. Structure-function studies have determined specific regions of the molecule to be important for GHR binding.
Mechanism of action
After GH binding to the GHR, the complex is internalized. Surprisingly, both pegvisomant and the non-pegylated GHR antagonist binds to the GHR with approximately the same affinity as GH, form dimers, and are internalized. It was argued that the GHR antagonist with eight amino acid substitutions in GH site 1 would result in molecules that would bind to the GHR with increased affinity. However, of the eight amino acid changes made within binding site 1, two (namely lysine to alanine and lysine to arginine at positions 168 and 172, respectively) are critical for site 1 binding to the GHR. Pegylation of these residues in the native molecule would block or sterically hinder binding of the antagonist to the first GHR. Thus, substitution of these residues removes potential pegylation sites within binding site 1 and, thus, ensures that site 1 of pegvisomant remains accessible to the GHR.
Mechanism of action
After GH binding to the GHR, the complex is internalized. Surprisingly, both pegvisomant and the non-pegylated GHR antagonist binds to the GHR with approximately the same affinity as GH, form dimers, and are internalized. It was argued that the GHR antagonist with eight amino acid substitutions in GH site 1 would result in molecules that would bind to the GHR with increased affinity. However, of the eight amino acid changes made within binding site 1, two (namely lysine to alanine and lysine to arginine at positions 168 and 172, respectively) are critical for site 1 binding to the GHR. Pegylation of these residues in the native molecule would block or sterically hinder binding of the antagonist to the first GHR. Thus, substitution of these residues removes potential pegylation sites within binding site 1 and, thus, ensures that site 1 of pegvisomant remains accessible to the GHR.
0 Comments
Post a Comment