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Title: Structure-activity relationships and solution conformation of SALMFamide neuropeptides
Author: Otara, Claire Bochaberi
ISNI:       0000 0004 2745 175X
Awarding Body: University of London
Current Institution: Queen Mary, University of London
Date of Award: 2007
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The SALMFamides SI (GFNSALMFamide) and S2 (SGPYSFNSGLTFamide) are neuropeptides that act as muscle relaxants in the starfish, with S2 ten times more potent than S 1. The aim of this study was to investigate the structural basis for this difference in potency. Synthetic analogues of SI and S2 were synthesized with the N-terminal SGPY sequence of S2 removed from S2 (SS2) and added to SI (LS 1) or with the penultimate amino-acid residues exchanged between SI and S2, SI (T) and S2(M). Analysis of the effects of SI, S2, LS 1, SS2, SI (T) and S2(M) on starfish cardiac stomach and tube preparations indicated that sequence differences in the C-terminal region of S 1 and S2 are the primary determinants ofS2's increased potency compared to SI and not the presence and absence of the N-terminal SGPY sequence in S2 and SI, respectively. To further investigate the structural basis for the differing potencies of SI and S2, the solution conformations of SI, S2, LS 1, SS2, SI (T) and S2(M) were investigated using CD and IH NMR spectroscopy. All the peptides except S2 and LSl have a random coil conformation in water. Interestingly, however, S2 has a single well-defmed conformation with a main-chain RMSD of 0.s03A for residues 2-11, comprising three loops in which aromatic side-chains form hydrophobic clusters with side-chains of other non-polar amino acids. In contrast, LS 1 has a single loop in its C-terminal region with an RMSD of 0.909 A for residues 6-12, which results from clustering of the hydrophobic side-chains ofPhe12, Met 11 , LeulO and Phe6• The remarkably well-defmed conformation of S2 is unusual amongst neuropeptides of comparable size without disulphide bridges. The N-terminal region of S2 (SGPy) may be important for induction and stabilisation of the conformation adopted by S2 in water.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available