Of many drug candidates designed for treatment of type II diabetes, an exendin‐4 (EX‐4) analog from the substitutions of both β‐Asp for Glu3 and Tyr for Gln13 of EX‐4 was found to have a prolongation in biological half life, an increase in cell proliferation and a remarkable improvement in reducing blood glucose with respect to EX‐4. In this study, we applied CD and NMR approaches to characterize the structures of this active EX‐4 analog in water, trifluoroethanol (TFE) aqueous solution, and dodecylphosphocholine (DPC) micelles and compared the results of the EX‐4 analog with those of EX‐4. Both EX‐4 peptides adopt α‐helix structures with the N‐termini disordered and the C‐terminal parts folded as hydrophobic clusters in these media. However, the analog has a longer helical extension in the N‐terminal part than EX‐4. The increasing helical turns may favor affinity for extracellular domain of glucagon‐like peptide‐1 receptor and accurate positioning of the crucial N‐terminal residues in the transmembrane domains of the receptor. The analog has a stronger propensity to aggregate than the native EX‐4, which is attributed to more coiled‐coil interaction in the analog than in its native type. We also probed the association of EX‐4 and its analog to DPC micelles and observed micelle‐induced insertion of both peptides with their N‐ and C‐termini as well as the central parts embedded in micelles and the residues near Asp9 and the residues around Trp25‐Ser32 more water exposed. A single‐step ligand‐receptor binding model was suggested based on the analysis of these results. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 348–357, 2011.