A NMR investigation in H2O, TFE and DMSO of a conformationally constrained, potent decapeptide agonist of human C5a, YSFKDMPLaR(C5a65-74, Y65, F67, P71, D-Ala73) showed that its N-terminal region(YSFKD) exhibited an extended backbone conformation in H2O and a more twisted conformation in both TFE/H2O (30:70, v/v; referred to as TFE) and DMSO. The C-terminal region (MPLaR) of the peptide adopted compact, turn-like structures. In H2O, the C-terminal region adopted a type II β-turn or a distorted type V/II β-turn involving residues PLaR. In the distorted type V/II β-turn, Leu72 exhibited a conformation typical of a type V β-turn, whereas D-Ala73 exhibited a conformation typical of a type II β-turn. The distorted type V/II β-turn overlapped with an inverse γ-turn involving residues MPL. In DMSO, the C-terminal region had the analogous inverse γ-turn and the V/IIβ-turn found in H2O. In many of the DMSO structures, two inverse γ-turns in the MPL and PLa positions formed a double-inverseγ-turn. None of the turns observed in H2O were present in TFE. However, in TFE, the PLa residues formed an inverse γ-turn. Overall, the turn-like structural motifs in the C-terminal region of the peptide in both H2O and DMSO (but not in TFE) agreed with the biologically important conformations obtained earlier by the structure-function analysis of a panel of C5a agonist peptides. These motifs may represent key structural elements important for C5a agonist activity and may be used to design the next generation of C5a agonist and antagonist analogues.