Abstract
Recently, we cloned many of the bullfrog neuropeptide G protein-coupled receptors (GPCRs), including receptors for vasotocin (VT), mesotocin, gonadotropin-releasing hormone (GnRH), neurotensin, apelin, and metastin. Bullfrog GPCRs usually have high affinity for bullfrog ligands but relatively low affinity for mammalian ligands. Reciprocally, synthetic agonists and antagonists developed based upon mammalian ligands display lower affinity at bullfrog receptors. Studies using chimeric or domain-swapped receptors indicate that the motifs responsible for differential ligand selectivity usually reside within transmembrane domain 6 (TMD6)-extracellular loop 3 (ECL3)-transmembrane domain 7 (TMD7). Triple mutation of mammalian V1aR (Phe 6.51 to Tyr, Ile 6.53 to Thr, and Pro 7.33 to Thr) increases VT affinity but greatly reduces arginine vasopressin affinity. This binding profile is similar to that of bullfrog VT1R. Changing just three amino acids in the bullfrog GnRH receptor-1 (i.e. Ser-Gln-Ser in the ECL3) to those found in the type-I mammalian GnRH receptor (i.e. Ser-Glu-Pro) reverses GnRH selectivity. In conclusion, specific receptor motifs that govern ligand selectivity can be determined by comparative molecular analyses of GPCRs and their ligands. Such analysis provides clues for understanding how GPCRs maintain high affinity to their authentic ligands.
| Original language | English |
|---|---|
| Pages (from-to) | 98-107 |
| Number of pages | 10 |
| Journal | General and Comparative Endocrinology |
| Volume | 153 |
| Issue number | 1-3 |
| DOIs | |
| Publication status | Published - 2007 Aug 1 |
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Keywords
- Coevolution
- G protein-coupled receptors
- Ligand selectivity
- Neuropeptides
ASJC Scopus subject areas
- Endocrinology
Cite this
Molecular evolution of neuropeptide receptors with regard to maintaining high affinity to their authentic ligands. / Cho, Hyun Ju; Acharjee, Sujata; Moon, Mi Jin; Oh, Da Young; Vaudry, Hubert; Kwon, Hyuk Bang; Seong, Jae Young.
In: General and Comparative Endocrinology, Vol. 153, No. 1-3, 01.08.2007, p. 98-107.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Molecular evolution of neuropeptide receptors with regard to maintaining high affinity to their authentic ligands
AU - Cho, Hyun Ju
AU - Acharjee, Sujata
AU - Moon, Mi Jin
AU - Oh, Da Young
AU - Vaudry, Hubert
AU - Kwon, Hyuk Bang
AU - Seong, Jae Young
PY - 2007/8/1
Y1 - 2007/8/1
N2 - Recently, we cloned many of the bullfrog neuropeptide G protein-coupled receptors (GPCRs), including receptors for vasotocin (VT), mesotocin, gonadotropin-releasing hormone (GnRH), neurotensin, apelin, and metastin. Bullfrog GPCRs usually have high affinity for bullfrog ligands but relatively low affinity for mammalian ligands. Reciprocally, synthetic agonists and antagonists developed based upon mammalian ligands display lower affinity at bullfrog receptors. Studies using chimeric or domain-swapped receptors indicate that the motifs responsible for differential ligand selectivity usually reside within transmembrane domain 6 (TMD6)-extracellular loop 3 (ECL3)-transmembrane domain 7 (TMD7). Triple mutation of mammalian V1aR (Phe 6.51 to Tyr, Ile 6.53 to Thr, and Pro 7.33 to Thr) increases VT affinity but greatly reduces arginine vasopressin affinity. This binding profile is similar to that of bullfrog VT1R. Changing just three amino acids in the bullfrog GnRH receptor-1 (i.e. Ser-Gln-Ser in the ECL3) to those found in the type-I mammalian GnRH receptor (i.e. Ser-Glu-Pro) reverses GnRH selectivity. In conclusion, specific receptor motifs that govern ligand selectivity can be determined by comparative molecular analyses of GPCRs and their ligands. Such analysis provides clues for understanding how GPCRs maintain high affinity to their authentic ligands.
AB - Recently, we cloned many of the bullfrog neuropeptide G protein-coupled receptors (GPCRs), including receptors for vasotocin (VT), mesotocin, gonadotropin-releasing hormone (GnRH), neurotensin, apelin, and metastin. Bullfrog GPCRs usually have high affinity for bullfrog ligands but relatively low affinity for mammalian ligands. Reciprocally, synthetic agonists and antagonists developed based upon mammalian ligands display lower affinity at bullfrog receptors. Studies using chimeric or domain-swapped receptors indicate that the motifs responsible for differential ligand selectivity usually reside within transmembrane domain 6 (TMD6)-extracellular loop 3 (ECL3)-transmembrane domain 7 (TMD7). Triple mutation of mammalian V1aR (Phe 6.51 to Tyr, Ile 6.53 to Thr, and Pro 7.33 to Thr) increases VT affinity but greatly reduces arginine vasopressin affinity. This binding profile is similar to that of bullfrog VT1R. Changing just three amino acids in the bullfrog GnRH receptor-1 (i.e. Ser-Gln-Ser in the ECL3) to those found in the type-I mammalian GnRH receptor (i.e. Ser-Glu-Pro) reverses GnRH selectivity. In conclusion, specific receptor motifs that govern ligand selectivity can be determined by comparative molecular analyses of GPCRs and their ligands. Such analysis provides clues for understanding how GPCRs maintain high affinity to their authentic ligands.
KW - Coevolution
KW - G protein-coupled receptors
KW - Ligand selectivity
KW - Neuropeptides
UR - http://www.scopus.com/inward/record.url?scp=34547095506&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547095506&partnerID=8YFLogxK
U2 - 10.1016/j.ygcen.2006.12.013
DO - 10.1016/j.ygcen.2006.12.013
M3 - Article
C2 - 17286976
AN - SCOPUS:34547095506
VL - 153
SP - 98
EP - 107
JO - General and Comparative Endocrinology
JF - General and Comparative Endocrinology
SN - 0016-6480
IS - 1-3
ER -