Abstract
Defining key differences between agonist and antagonist binding to hormone receptors is important and will aid rational drug design. Glu1.35 in transmembrane helix 1 (TM1) of the human oxytocin receptor (OTR) is absolutely conserved in all OTRs cloned to date. We establish that Glu1.35 is critical for high affinity binding of agonists (full and partial) but is not required for antagonist binding (peptide or non-peptide). Consequently, the mutant receptor [E1.35A]OTR exhibited markedly decreased OT affinity (>1200-fold) and disrupted second messenger generation. Substitutions of Glu1.35 by Asp, Gln or Arg were incapable of supporting wild-type OTR agonist binding or signaling. Molecular modeling revealed that Glu1.35 projects into the receptor's central binding crevice and provides agonist-specific contacts not utilized by antagonists. This study explains why Glu is absolutely conserved at residue-1.35 in all receptors binding OT and related peptides, and provides molecular insight into key differences between agonist-receptor and antagonist-receptor binding modes.
| Original language | English |
|---|---|
| Pages (from-to) | 20-27 |
| Number of pages | 8 |
| Journal | Molecular and Cellular Endocrinology |
| Volume | 333 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 10 Feb 2011 |
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Keywords
- GPCR
- Oxytocin
- Oxytocin receptor
- Peptide hormone
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Agonist-specific requirement for a glutamate in transmembrane helix 1 of the oxytocin receptor. / Wootten, Denise L.; Simms, John; Massoura, Amelia J.; Trim, Julie E.; Wheatley, Mark.
In: Molecular and Cellular Endocrinology, Vol. 333, No. 1, 10.02.2011, p. 20-27.Research output: Contribution to journal › Article
TY - JOUR
T1 - Agonist-specific requirement for a glutamate in transmembrane helix 1 of the oxytocin receptor
AU - Wootten, Denise L.
AU - Simms, John
AU - Massoura, Amelia J.
AU - Trim, Julie E.
AU - Wheatley, Mark
PY - 2011/2/10
Y1 - 2011/2/10
N2 - Defining key differences between agonist and antagonist binding to hormone receptors is important and will aid rational drug design. Glu1.35 in transmembrane helix 1 (TM1) of the human oxytocin receptor (OTR) is absolutely conserved in all OTRs cloned to date. We establish that Glu1.35 is critical for high affinity binding of agonists (full and partial) but is not required for antagonist binding (peptide or non-peptide). Consequently, the mutant receptor [E1.35A]OTR exhibited markedly decreased OT affinity (>1200-fold) and disrupted second messenger generation. Substitutions of Glu1.35 by Asp, Gln or Arg were incapable of supporting wild-type OTR agonist binding or signaling. Molecular modeling revealed that Glu1.35 projects into the receptor's central binding crevice and provides agonist-specific contacts not utilized by antagonists. This study explains why Glu is absolutely conserved at residue-1.35 in all receptors binding OT and related peptides, and provides molecular insight into key differences between agonist-receptor and antagonist-receptor binding modes.
AB - Defining key differences between agonist and antagonist binding to hormone receptors is important and will aid rational drug design. Glu1.35 in transmembrane helix 1 (TM1) of the human oxytocin receptor (OTR) is absolutely conserved in all OTRs cloned to date. We establish that Glu1.35 is critical for high affinity binding of agonists (full and partial) but is not required for antagonist binding (peptide or non-peptide). Consequently, the mutant receptor [E1.35A]OTR exhibited markedly decreased OT affinity (>1200-fold) and disrupted second messenger generation. Substitutions of Glu1.35 by Asp, Gln or Arg were incapable of supporting wild-type OTR agonist binding or signaling. Molecular modeling revealed that Glu1.35 projects into the receptor's central binding crevice and provides agonist-specific contacts not utilized by antagonists. This study explains why Glu is absolutely conserved at residue-1.35 in all receptors binding OT and related peptides, and provides molecular insight into key differences between agonist-receptor and antagonist-receptor binding modes.
KW - GPCR
KW - Oxytocin
KW - Oxytocin receptor
KW - Peptide hormone
UR - http://www.scopus.com/inward/record.url?scp=78651427803&partnerID=8YFLogxK
UR - https://www.sciencedirect.com/science/article/pii/S0303720710005575?via%3Dihub
U2 - 10.1016/j.mce.2010.11.029
DO - 10.1016/j.mce.2010.11.029
M3 - Article
C2 - 21130837
AN - SCOPUS:78651427803
VL - 333
SP - 20
EP - 27
IS - 1
ER -