Molecular basis for high affinity and selectivity of peptide antagonist, Bantag-1, for the orphan BB3 receptor.

  title={Molecular basis for high affinity and selectivity of peptide antagonist, Bantag-1, for the orphan BB3 receptor.},
  author={Taichi Nakamura and Irene Ramos-{\'A}lvarez and Tatiana Iordanskaia and Paola Moreno and Samuel A. Mantey and Robert T. Jensen},
  journal={Biochemical pharmacology},
Bombesin-receptor-subtype-3 (BB3 receptor) is a G-protein-coupled-orphan-receptor classified in the mammalian Bombesin-family because of high homology to gastrin-releasing peptide (BB2 receptor)/neuromedin-B receptors (BB1 receptor). There is increased interest in BB3 receptor because studies primarily from knockout-mice suggest it plays roles in energy/glucose metabolism, insulin-secretion, as well as motility and tumor-growth. Investigations into its roles in physiological/pathophysiological… 
Development and Characterization of a Novel, High-Affinity, Specific, Radiolabeled Ligand for BRS-3 Receptors
The peptide antagonist Bantag-1 had >10,000-fold selectivity for human BRS-3 (hB RS-3) over other mammalian Bn receptors (BnRs) [i.e., gastrin-releasing peptide receptor (GRPR) and neuromedin B receptor (NMBR] and it was radiolabeled to high specific activity and found to bind with high affinity/specificity to hBRS- 3.
AM-37 and ST-36 Are Small Molecule Bombesin Receptor Antagonists
AM-37 and ST-36 function as small molecule BB receptor antagonists and reduce the growth of lung cancer cells that have BBR.
Understanding Peptide Binding in Class A G Protein-Coupled Receptors
The knowledge of recently crystalized peptide-GPCR complexes, previously accumulated peptide structure-activity relationship studies, receptor mutagenesis, and sequence alignment are integrated to better understand peptide binding to the transmembrane cavity of class A GPCRs.
Neuropeptide G Protein-Coupled Receptors as Oncotargets
This review will focus on how BB, NTS, VIP, and SST receptors can facilitate the early detection and treatment of cancer.
Peptide receptors as cancer drug targets
  • T. Moody
  • Chemistry, Medicine
    Annals of the New York Academy of Sciences
  • 2019
How GPCRs for VIP and BB are molecular targets for early detection and treatment of cancer is focused on.
Bombesin, endothelin, neurotensin and pituitary adenylate cyclase activating polypeptide cause tyrosine phosphorylation of receptor tyrosine kinases
GRCR antagonists and tyrosine kinase inhibitors are useful agents to prevent RTK transactivation and inhibit proliferation of cancer cells.


Molecular Basis for Agonist Selectivity and Activation of the Orphan Bombesin Receptor Subtype 3 Receptor
These results demonstrate that Val101, His107, Gly112, and Arg127 in the EC2/adjacent upper TMs of BRS-3 are critical for the high BRS3 selectivity of peptides 4 and 1, and amino-aromatic ligand/receptor interactions with peptide 4 arecritical for both binding and activation.
Molecular Basis for Selectivity of High Affinity Peptide Antagonists for the Gastrin-releasing Peptide Receptor*
It is demonstrated that Thr297, Phe302, and Ser305 of the fourth EC domain of GRPR are the critical residues for determining GRPR selectivity and suggest that both receptor-ligand cation-π interactions and hydrogen bonding are important for their high affinity interaction.
Pharmacology of putative selective hBRS-3 receptor agonists for human bombesin receptors (BnR): Affinities, potencies and selectivity in multiple native and BnR transfected cells
Results show that peptide #3 is the preferred hBRS-3 agonist for studies at present, although its selectivity of only 100-fold may limit its utility in some cases.
Development of Bombesin Analogs with Conformationally Restricted Amino Acid Substitutions with Enhanced Selectivity for the Orphan Receptor Human Bombesin Receptor Subtype 3
A more selective hBRS-3 ligand is attempted by using two strategies: substitutions on phenyl ring of Apa11 and the substitution of other conformationally restricted amino acids into position 11 of [d-Tyr6,β-Ala11,Phe13,Nle14]Bn(6-14).
Molecular Basis for the Selectivity of the Mammalian Bombesin Peptide, Neuromedin B, for Its Receptor
Receptor-chimeric studies showed that NMBR selectivity for NMB was primarily determined by differences in the third extracellular (EC3) regions of GRPR-NMBR and adjacent upper-transmembrane-5 (TM5) region.
Ability of Various Bombesin Receptor Agonists and Antagonists to Alter Intracellular Signaling of the Human Orphan Receptor BRS-3*
Results show that hBRS-3 receptor activation increases phospholipase C activity, which causes generation of inositol phosphates and changes in [Ca2+] i and is also coupled to tyrosine kinase activation, but is not coupled to adenylate cyclase activation or inhibition.
Rational Design of a Peptide Agonist That Interacts Selectively with the Orphan Receptor, Bombesin Receptor Subtype 3*
This study has attempted to identify BRS-3 selective ligands using a strategy of rational peptide design with the substitution of conformationally restricted amino acids into the prototype ligand [d-Tyr6,β-Ala11,Phe13,Nle14]Bn-(6–14) or its d-Phe6 analogue.
The molecular basis for high affinity of a universal ligand for human bombesin receptor (BnR) family members.
Results show that high affinity for Univ.Lig by human Bn-receptors requires positively charged amino acids in extracellular (EC)-domain 4 and to a lesser extent EC2 and EC3 suggesting charge-charge interactions may be particularly important for determining the general high affinity of this ligand.
Identification of a unique ligand which has high affinity for all four bombesin receptor subtypes.
Results demonstrate 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) is a unique ligand with high affinity for all subtypes of bombesin receptors.
ML-18 is a non-peptide bombesin receptor subtype-3 antagonist which inhibits lung cancer growth
ML-18 is a nonpeptide BRS-3 antagonist that should serve as a template to improve potency and selectivity and inhibit the proliferation of lung cancer cells.