MOLECULAR MODELING OF THE ENDOGENOUS PEPTIDE LEU-SER-ALA-LEU, PINDOLOL, 5-HYDROXYTRYPTAMINE AND THEIR INTERACTIONS WITH THE HUMAN 5-HYDROXYTRYPTAMINE(1B) (5-HT1B) RECEPTOR

Molecular modeling techniques were used to build a three-dimensional m odel of the human S-HT1B receptor. The receptor model was used to exam ine receptor interactions of 5-hydroxytryptamine (serotonin), (S)pindo lol 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 biolo gically active, and propose that a negatively charged residue conserve d 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 molecul ar dynamics simulations that were started with the N-terminus of LSAL positioned close to Asp352 in transmembrane helix 7. The model suggest s that Asp352 in transmembrane helix 7 may act as a counter-ion for th e positively charged N-terminus, and that the side chains of Tyr109 (t ransmembrane helix 2) and Trp 125 (transmembrane helix 3) may form hyd rogen bonds with the negatively charged C-terminus of LSAL.