Calcitonin Family Related Drug Discovery Products
Creative Biolabs has the assays you can rely on for high throughput screening, lead optimization, characterizing and discovering targets, and uncovering the complexity of disease pathways. We can offer membrane protein in vitro assay kits that save valuable laboratory time and is ideal for high throughput screening.
Membrane protein stable cell lines are widely used in many areas of biomedical research. Creative Biolabs can offer membrane protein stable cell lines to stablish in vitro models for High Throughput Screening.
Creative Biolabs offers high-quality, innovative tools to help research groups accelerate membrane protein drug discovery. They can be found by targets. If there is no product that meets your needs, please contact us.
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. It belongs to a group of peptides that all work on an unusual family of receptors. These receptors are composed of a protein termed RAMP, which is crucial for normal operation, and a calcitonin receptor-like receptor (CLR). Due to its potent vasodilator properties, CGRP has protective mechanisms that are essential for physiological and pathological illnesses affecting the circulatory system and wound healing. Pain circuits are hypothesized to involve sensory nerves since they are the main source of CGRP release.
Creative Biolabs offers high-quality assays and products to help research groups accelerate drug discovery and development projects of calcitonin family:
Overview of Calcitonin Receptor
Regarding their modulation by RAMPs, the class B receptors calcitonin and calcitonin-like receptors, CTR and CLR, have received the most attention. The alteration of CTR and CLR's binding preferences for the six calcitonin family peptides-calcitonin (CT), amylin, calcitonin gene-related peptides, adrenomedullin, and adrenomedullin 2/intermedin-is the most significant effect of the RAMPs on CTR and CLR.
- CALCR (CTR)
The cryo-EM structure of full-length CTR with bound sCT agonist and Gs heterotrimer exhibited significant inter-domain flexibility and demonstrated how the agonist binds the TMD. Since the CTR and CLR sequences are identical, it is likely that the RAMPs interact with ECL2 and do not directly interact with the N-terminal part of the peptide. This is supported by the RAMP TMD occupying the same TM3/4/5 location as the CGRP receptor. Peptide selectivity may be influenced by the modulation of inter-domain dynamics caused by the RAMPs as well as direct manipulation of the CTR TMD. The RAMPs are likely to limit the flexibility of the CTR ECD relative to the TMD.
Fig.1 Structures of sCT-bound CTR. (Pioszak & Hay, 2020)
- CALCRL (CLR)
The CLR is a member of the class B family of G protein-coupled receptors (GPCRs). The RAMP family is made up of the proteins RAMP1, RAMP2, and RAMP3. The CGRP receptor produced by RAMP1 and CLR heterodimerization can be blocked by the shortened peptide CGRP8-37 and nonpeptide CGRP antagonists. The interaction of CLR and RAMP2 results in the first adrenomedullin receptor (AM1 receptor), while the association of CLR and RAMP3 results in the second adrenomedullin receptor (AM2 receptor).
Fig.2 CGRP receptor-mediated intracellular signaling. (Russell, 2014)
Calcitonin Receptor Drug Discovery
Expanded potential for targeting with small compounds, peptides, and antibodies are provided via the RAMP-GPCR interface. This was first proven with the creation of small-molecule CGRP receptor antagonists for migraine that bind to RAMP1 and occupy the pocket in the CLR ECD to enable selectivity. It should be able to create allosteric modulators that regulate peptide binding and signaling by attaching to different sites at the RAMP-CLR/CTR interface.
References
- Pioszak, A.A., & Hay, D.L. RAMPs as allosteric modulators of the calcitonin and calcitonin-like class BG protein-coupled receptors. Advances in Pharmacology. 2020, 88: 115-141.
- Russell, F.A.; et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiological reviews. 2014, 94(4): 1099-1142.
