title: Type II Turn of Receptor-bound Salmon Calcitonin Revealed by X-ray Crystallography.
abstract: Calcitonin is a peptide hormone consisting of 32 amino acid residues and the calcitonin receptor is a Class B G protein-coupled receptor (GPCR). The crystal structure of the human calcitonin receptor ectodomain (CTR ECD) in complex with a truncated analogue of salmon calcitonin ([BrPhe(22)]sCT(8-32)) has been determined to 2.1-Å resolution. Parallel analysis of a series of peptide ligands showed that the rank order of binding of the CTR ECD is identical to the rank order of binding of the full-length CTR, confirming the structural integrity and relevance of the isolated CTR ECD. The structure of the CTR ECD is similar to other Class B GPCRs and the ligand binding site is similar to the binding site of the homologous receptors for the calcitonin gene-related peptide (CGRP) and adrenomedulin (AM) recently published (Booe, J. M., Walker, C. S., Barwell, J., Kuteyi, G., Simms, J., Jamaluddin, M. A., Warner, M. L., Bill, R. M., Harris, P. W., Brimble, M. A., Poyner, D. R., Hay, D. L., and Pioszak, A. A. (2015) Mol. Cell 58, 1040-1052). Interestingly the receptor-bound structure of the ligand [BrPhe(22)]sCT(8-32) differs from the receptor-bound structure of the homologous ligands CGRP and AM. They all adopt an extended conformation followed by a C-terminal β turn, however, [BrPhe(22)]sCT(8-32) adopts a type II turn (Gly(28)-Thr(31)), whereas CGRP and AM adopt type I turns. Our results suggest that a type II turn is the preferred conformation of calcitonin, whereas a type I turn is the preferred conformation of peptides that require RAMPs; CGRP, AM, and amylin. In addition the structure provides a detailed molecular explanation and hypothesis regarding ligand binding properties of CTR and the amylin receptors.
authors.affiliation: From Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark evjh@novonordisk.com.
authors.forename: Eva
authors.initials: E
authors.lastname: Johansson
authors.affiliation: From Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Jakob Lerche
authors.initials: JL
authors.lastname: Hansen
authors.affiliation: From Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Ann Maria Kruse
authors.initials: AM
authors.lastname: Hansen
authors.affiliation: From Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Allan Christian
authors.initials: AC
authors.lastname: Shaw
authors.affiliation: From Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Becker
authors.affiliation: From Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Lauge
authors.initials: L
authors.lastname: Schäffer
authors.affiliation: From Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Reedtz-Runge
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D029941:Fish Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D018003:Receptors, Calcitonin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012474:Salmon
chemical_list: D029941:Fish Proteins; D018003:Receptors, Calcitonin; D002116:Calcitonin
keywords: G protein-coupled receptor (GPCR); amylin; calcitonin; crystal structure; peptide conformation; peptide hormone; peptide interaction