PMID- 25180755
OWN - NLM
STAT- MEDLINE
DCOM- 20150518
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 9
DP  - 2014
TI  - Glucagon-like peptide-1 receptor ligand interactions: structural cross talk 
      between ligands and the extracellular domain.
PG  - e105683
LID - 10.1371/journal.pone.0105683 [doi]
LID - e105683
AB  - Activation of the glucagon-like peptide-1 receptor (GLP-1R) in pancreatic beta-cells 
      potentiates insulin production and is a current therapeutic target for the 
      treatment of type 2 diabetes mellitus (T2DM). Like other class B G 
      protein-coupled receptors (GPCRs), the GLP-1R contains an N-terminal 
      extracellular ligand binding domain. N-terminal truncations on the peptide 
      agonist generate antagonists capable of binding to the extracellular domain, but 
      not capable of activating full length receptor. The main objective of this study 
      was to use Hydrogen/deuterium exchange (HDX) to identify how the amide hydrogen 
      bonding network of peptide ligands and the extracellular domain of GLP-1R 
      (nGLP-1R) were altered by binding interactions and to then use this platform to 
      validate direct binding events for putative GLP-1R small molecule ligands. The 
      HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R) 
      peptide ligands indicates that the antagonist exendin-4[9-39] is significantly 
      destabilized in the presence of nonionic detergents as compared to the agonist 
      exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and 
      exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to 
      Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R). 
      In addition we show hydrogen bonding network stabilization on nGLP-1R in response 
      to ligand binding, and validate direct binding events with the extracellular 
      domain of the receptor for putative GLP-1R small molecule ligands.
FAU - West, Graham M
AU  - West GM
AD  - Department of Molecular Therapeutics, The Scripps Research Institute, Scripps 
      Florida, Jupiter, Florida, United States of America; Mass Spectrometry and 
      Proteomics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, 
      United States of America.
FAU - Willard, Francis S
AU  - Willard FS
AD  - Quantitative Biology, Lilly Research Laboratories, Eli Lilly and Company, 
      Indianapolis, Indiana, United States of America.
FAU - Sloop, Kyle W
AU  - Sloop KW
AD  - Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, 
      Indianapolis, Indiana, United States of America.
FAU - Showalter, Aaron D
AU  - Showalter AD
AD  - Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, 
      Indianapolis, Indiana, United States of America.
FAU - Pascal, Bruce D
AU  - Pascal BD
AD  - Department of Molecular Therapeutics, The Scripps Research Institute, Scripps 
      Florida, Jupiter, Florida, United States of America; Informatics Core, The 
      Scripps Research Institute, Scripps Florida, Jupiter, Florida, United States of 
      America.
FAU - Griffin, Patrick R
AU  - Griffin PR
AD  - Department of Molecular Therapeutics, The Scripps Research Institute, Scripps 
      Florida, Jupiter, Florida, United States of America.
LA  - eng
GR  - R01 GM084041/GM/NIGMS NIH HHS/United States
GR  - S10 RR027270/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140902
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Ligands)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Glucagon)
RN  - 0 (Small Molecule Libraries)
RN  - 0 (Venoms)
RN  - 9P1872D4OL (Exenatide)
SB  - IM
MH  - Amino Acid Sequence
MH  - Crystallography, X-Ray
MH  - Deuterium Exchange Measurement
MH  - Exenatide
MH  - Glucagon-Like Peptide-1 Receptor
MH  - Ligands
MH  - Molecular Sequence Data
MH  - Peptides/chemistry/metabolism
MH  - Protein Structure, Tertiary
MH  - Receptors, Glucagon/*chemistry/*metabolism
MH  - Small Molecule Libraries/chemistry/metabolism
MH  - Venoms/chemistry/metabolism
PMC - PMC4152014
COIS- Competing Interests: The authors have read the journal's policy and have the 
      following conflicts: FSW, KWS, and ADS are paid employees of Eli Lilly and 
      Company and may own company stock or possess stock options. This does not alter 
      the authors' adherence to PLOS ONE policies on sharing data and materials.
EDAT- 2014/09/03 06:00
MHDA- 2015/05/20 06:00
PMCR- 2014/09/02
CRDT- 2014/09/03 06:00
PHST- 2014/05/12 00:00 [received]
PHST- 2014/07/23 00:00 [accepted]
PHST- 2014/09/03 06:00 [entrez]
PHST- 2014/09/03 06:00 [pubmed]
PHST- 2015/05/20 06:00 [medline]
PHST- 2014/09/02 00:00 [pmc-release]
AID - PONE-D-14-20318 [pii]
AID - 10.1371/journal.pone.0105683 [doi]
PST - epublish
SO  - PLoS One. 2014 Sep 2;9(9):e105683. doi: 10.1371/journal.pone.0105683. eCollection 
      2014.