PMID- 20529866
OWN - NLM
STAT- MEDLINE
DCOM- 20100920
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 32
DP  - 2010 Aug 6
TI  - 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.
PG  - 24508-18
LID - 10.1074/jbc.M110.135749 [doi]
AB  - 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. We developed 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 Tyr(145), adjacent to the first 
      transmembrane segment, as the site of labeling by the position 12 probe, and 
      receptor residue Tyr(205), 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 B G protein-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.
FAU - Chen, Quan
AU  - Chen Q
AD  - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 
      Scottsdale, Arizona 85259, USA.
FAU - Pinon, Delia I
AU  - Pinon DI
FAU - Miller, Laurence J
AU  - Miller LJ
FAU - Dong, Maoqing
AU  - Dong M
LA  - eng
GR  - R01 DK046577/DK/NIDDK NIH HHS/United States
GR  - R56 DK046577/DK/NIDDK NIH HHS/United States
GR  - DK46577/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100607
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (GLP1R protein, human)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Hormones)
RN  - 0 (Ligands)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Receptors, Glucagon)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - CHO Cells
MH  - Cricetinae
MH  - Cricetulus
MH  - Glucagon-Like Peptide 1/*chemistry
MH  - Glucagon-Like Peptide-1 Receptor
MH  - Hormones/chemistry
MH  - Humans
MH  - Ligands
MH  - Molecular Sequence Data
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - Receptors, G-Protein-Coupled/chemistry
MH  - Receptors, Glucagon/*chemistry
MH  - Structure-Activity Relationship
PMC - PMC2915687
EDAT- 2010/06/10 06:00
MHDA- 2010/09/21 06:00
PMCR- 2011/08/06
CRDT- 2010/06/10 06:00
PHST- 2010/06/10 06:00 [entrez]
PHST- 2010/06/10 06:00 [pubmed]
PHST- 2010/09/21 06:00 [medline]
PHST- 2011/08/06 00:00 [pmc-release]
AID - S0021-9258(20)66317-7 [pii]
AID - M110.135749 [pii]
AID - 10.1074/jbc.M110.135749 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Aug 6;285(32):24508-18. doi: 10.1074/jbc.M110.135749. Epub 2010 
      Jun 7.