7p0f

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Crystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0028125

Structural highlights

7p0f is a 1 chain structure with sequence from Escherichia coli K-12 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.85Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.RAMP1_HUMAN Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for calcitonin-gene-related peptide (CGRP) together with CALCRL.^[1] CALRL_HUMAN Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.^[2]

Publication Abstract from PubMed

A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure-activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.

Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein-Ligand Complexes.,Cansfield AD, Ator MA, Banerjee J, Bestwick M, Bortolato A, Brown GA, Brown J, Butkovic K, Cansfield JE, Christopher JA, Congreve M, Cseke G, Deflorian F, Dugan B, Hunjadi MP, Hutinec A, Inturi TK, Landek G, Mason J, O'Brien A, Ott GR, Rupcic R, Saxty G, Southall SM, Zadravec R, Watson SP ACS Chem Neurosci. 2022 Mar 16;13(6):751-765. doi: 10.1021/acschemneuro.1c00696. , Epub 2022 Mar 4. PMID:35245037^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. 1998 May 28;393(6683):333-9. PMID:9620797 doi:10.1038/30666
↑ Kusano S, Kukimoto-Niino M, Hino N, Ohsawa N, Okuda K, Sakamoto K, Shirouzu M, Shindo T, Yokoyama S. Structural basis for extracellular interactions between calcitonin receptor-like receptor and receptor activity-modifying protein 2 for adrenomedullin-specific binding. Protein Sci. 2012 Feb;21(2):199-210. doi: 10.1002/pro.2003. Epub 2011 Dec 28. PMID:22102369 doi:10.1002/pro.2003
↑ Cansfield AD, Ator MA, Banerjee J, Bestwick M, Bortolato A, Brown GA, Brown J, Butkovic K, Cansfield JE, Christopher JA, Congreve M, Cseke G, Deflorian F, Dugan B, Hunjadi MP, Hutinec A, Inturi TK, Landek G, Mason J, O'Brien A, Ott GR, Rupcic R, Saxty G, Southall SM, Zadravec R, Watson SP. Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein-Ligand Complexes. ACS Chem Neurosci. 2022 Mar 16;13(6):751-765. PMID:35245037 doi:10.1021/acschemneuro.1c00696