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Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74. | LitMetric

AI Article Synopsis

  • - The calcitonin gene-related peptide (CGRP) receptor is crucial for developing new migraine treatments, with promising antagonists BIBN4096BS and MK-0974 showing potential in clinical trials.
  • - The CGRP receptor is a complex of the calcitonin receptor-like receptor (CRL) and an accessory protein (RAMP1), with specific interactions forming the peptide-binding site and possibly the antagonist binding site as well.
  • - A study identified a mutant in the N-terminal domain of CLR and a mutation in RAMP1 that significantly lower the binding affinities for both antagonists, suggesting their binding occurs near the interface of these two protein components.

Article Abstract

The receptor for calcitonin gene-related peptide (CGRP) has been the target for the development of novel small molecule antagonists for the treatment of migraine. Two such antagonists, BIBN4096BS and MK-0974, have shown great promise in clinical trials and hence a deeper understanding of the mechanism of their interaction with the receptor is now required. The structure of the CGRP receptor is unusual since it is comprised of a hetero-oligomeric complex between the calcitonin receptor-like receptor (CRL) and an accessory protein (RAMP1). Both the CLR and RAMP1 components have extracellular domains which interact with each other and together form part of the peptide-binding site. It seems likely that the antagonist binding site will also be located on the extracellular domains and indeed Trp-74 of RAMP1 has been shown to form part of the binding site for BIBN4096BS. However, despite a chimeric study demonstrating the role of the N-terminal domain of CLR in antagonist binding, no specific residues have been identified. Here we carry out a mutagenic screen of the extreme N-terminal domain of CLR (residues 23-63) and identify a mutant, Met-42-Ala, which displays 48-fold lower affinity for BIBN4096BS and almost 900-fold lower affinity for MK-0974. In addition, we confirm that the Trp-74-Lys mutation at human RAMP1 reduces BIBN4096BS affinity by over 300-fold and show for the first time a similar effect for MK-0974 affinity. The data suggest that the non-peptide antagonists occupy a binding site close to the interface of the N-terminal domains of CLR and RAMP1.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824848PMC
http://dx.doi.org/10.1016/j.bbrc.2009.11.076DOI Listing

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