Spatial approximations between residues 6 and 12 in the amino-terminal region of glucagon-like peptide 1 and its receptor

A region critical for biological activity

Quan Chen, Delia I. Pinon, Laurence J Miller, Maoqing Dong

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Understanding the molecular basis of natural ligand binding and activation of the glucagon-like peptide 1 (GLP1) receptor may facilitate the development of agonist drugs useful for the management of type 2 diabetes mellitus. We previously reported molecular approximations between carboxyl-terminal residues 24 and 35 within GLP1 and its receptor. In this work, we have focused on the amino-terminal region of GLP1, known to be critical for receptor activation.Wedeveloped two high-affinity, full agonist photolabile GLP1 probes having sites of covalent attachment in positions 6 and 12 of the 30-residue peptide (GLP1(7-36)). Both probes bound to the receptor specifically and covalently labeled single distinct sites. Chemical and protease cleavage of the labeled receptor identified the juxtamembrane region of its amino-terminal domain as the region of covalent attachment of the position 12 probe, whereas the region of labeling by the position 6 probe was localized to the first extracellular loop. Radiochemical sequencing identified receptor residue Tyr145, adjacent to the first transmembrane segment, as the site of labeling by the position 12 probe, and receptor residue Tyr205, within the first extracellular loop, as the site of labeling by the position 6 probe. These data provide support for a common mechanism for natural ligand binding and activation of family BGprotein-coupled receptors. This region of interaction of peptide amino-terminal domains with the receptor may provide a pocket that can be targeted by small molecule agonists.

Original languageEnglish (US)
Pages (from-to)24508-24518
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number32
DOIs
StatePublished - Aug 6 2010

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Glucagon-Like Peptide 1
Bioactivity
Ligands
Peptides
Labeling
Type 2 Diabetes Mellitus
Peptide Hydrolases
Chemical activation
Pharmaceutical Preparations
Medical problems
Glucagon-Like Peptide-1 Receptor
Molecules
glucagon-like peptide 1 (7-36)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Spatial approximations between residues 6 and 12 in the amino-terminal region of glucagon-like peptide 1 and its receptor : A region critical for biological activity. / Chen, Quan; Pinon, Delia I.; Miller, Laurence J; Dong, Maoqing.

In: Journal of Biological Chemistry, Vol. 285, No. 32, 06.08.2010, p. 24508-24518.

Research output: Contribution to journalArticle

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