Structure

Cellular Domains

The amylin receptor, AMYR, has three domains: extracellular, transmembrane, and intracellular. The calcitonin receptor, CTR, and the receptor activity-modifying protein, RAMP, have both and . The ligand, amylin, binds within the transmembrane domain. The G protein is located . The location of each component of the amylin receptor is essential in determining structure and function.

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Receptor components

AMYR is a heterodimer of a calcitonin receptor (CTR) and a receptor activity-modifying protein (RAMP). There are three different RAMPs, RAMP1, RAMP2, and RAMP3, that compose AMY1R, AMY2R, and AMY3R.

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The two major ligands of the calcitonin receptor are calcitonin and amylin. In the absence of a RAMP, the calcitonin receptor has greater affinity for calcitonin than amylin, but because the , both calcitonin and amylin can bind to the CTR without any modification of the receptor. When the CTR is bound to a RAMP, the complex becomes the AMYR and has greater affinity for the relative to the calcitonin ligand.(REFERENCE NEEDED HERE******)

Sequence alignment of rat amylin and salmon calcitonin.

There are two required post-translational modifications of amylin in order for the ligand to have any bioactivity: (1) and (2) a between C2 and C7.

Binding Site Residues

There are water molecules present in the binding site between amylin and the calcitonin receptor that support the ligand-receptor interaction. Some water molecules interact with the amylin ligand and create water-bridged Hydrogen bonds between different ligand residues, such as the . Other water molecules create . The water molecules are present in the empty space located in the ligand binding site, and they are hypothesized to stabilize the active conformation of the calcitonin receptor when amylin is bound. Substitutions of polar residues involved with the water-bridged Hydrogen bond network to nonpolar residues causes a decrease in potency and affinity of amylin to the calcitonin receptor. (REFERENCE NEEDED HERE******)

There are . These bonds contribute to the functional phenotype of AMYR and also causes the end of the amylin ligand to be held in a flipped up position.

G Protein Activation

There are extensive nonpolar, . Here, Val322 and Leu323 of the CTR 2nd intracellular loop makes nonpolar interactions with Ile248 and Val249 back to itself as well as Leu388 of the Gα subunit. The . The 3rd intracellular loop has Arg180 hydrogen bonding to the Gln384 of the Gα subunit.

Function

Biological Relevance

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The functional pharmacology of AMYRs has relied on interference from differences between the behavior of CTRs in the presence and absence of RAMPs. Thus, understanding the structural basis for binding and selectivity of peptides to CTR and AMYRs is important for future drug discovery and development.

Diabetes

Amylin, as it is a part of the calcitonin peptide family, is heavily related to the regulation of homeostatic processes to relevant drug targets. Amylin is the target for the treatment of diabetes. Amylin is a neuroendocrine hormone that is synthesized and co-secreted with insulin. Insulin triggers glucose uptake which removes glucose from the bloodstream using it then for energy. Amylin works in negatively regulating (inhibiting) the formation of glucagon so that glucose polymers can continue to be broken down into the bloodstream for further energy storage and consumption. Therefore with the co-secretion of both amylin and insulin, it would aid in decreasing blood glucose levels thus becoming a predominant treatment plan for diabetic disorders, such as shown with the developing drug Pramlintide.

Pramlintide

Pramlintide, a peptide analog of human amylin, is FDA-approved for the treatment of insulin-requiring diabetes. Pramlintide is injected into the bloodstream by the beta cells of the pancreas along with insulin after a meal, aiding in the regulation of blood glucose by slowing gastric emptying, promoting satiety via hypothalamic receptors, and inhibiting secretion of glucagon which opposes the effects of insulin and amylin.

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