Molecular modeling of the endogenous peptide Leu-Ser-Ala-Leu, pindolol, 5-hydroxytryptamine and their interactions with the human 5-hydroxytryptamine1B (5-HT1B) receptor.
Molecular modeling techniques were used to build a three-dimensional model of the human 5-HT1B receptor. The receptor model was used to examine receptor interactions of 5-hydroxytryptamine (serotonin), (S)pindolol and of the tetrapeptide Leu-Ser-Ala-Leu (LSAL), which recently has been shown to interact specifically with the 5-HT1B receptor. We have assumed that the NH3(+)-LSAL-COO- form of the tetrapeptide is the biologically active, and propose that a negatively charged residue conserved among various species homologues of the 5-HT1B receptor may act as a counter-ion for the positively charged N-terminus of the tetrapeptide. The strongest LSAL-receptor interactions were obtained after molecular dynamics simulations that were started with the N-terminus of LSAL positioned close to Asp352 in transmembrane helix 7. The model suggests that Asp352 in transmembrane helix 7 may act as a counter-ion for the positively charged N-terminus, and that the side chains of Tyr109 (transmembrane helix 2) and Trp125 (transmembrane helix 3) may form hydrogen bonds with the negatively charged C-terminus of LSAL.
Department of Pharmacology, University of Tromsø, Norway.
K
K
Kristiansen
O
O
Edvardsen
S G
SG
Dahl
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000737:chemistry* / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism*; D010869:Pindolol / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity; D013816:Thermodynamics
C102005:5-HT-moduline; C470302:HTR1B protein, human; D008024:Ligands; D046911:Macromolecular Substances; D009479:Neuropeptides; D009842:Oligopeptides; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D010869:Pindolol