The hormone leptin is central to obesity, but the molecular processes underlying the activation of the leptin receptor are unknown. To further the understanding of the system, an atomic resolution structure of this cytokine type I receptor in the unbound inactive form and in the activated bound form is a necessity. Here, the solution state structures of two of the seven extracellular domains of the receptor are presented: the D2 and the D5CA domains. The latter is a double-mutant (C604A, C613A). The function of the D2 domain is unknown, but data indicate that it increases the signaling of the receptor, while the D5 domain is the central leptin-binding domain, implicated in the first steps of activation. Both domains are characterized by a fibronectin type III fold and both contain a conserved WSXWS motif (X represents an unconserved amino acid residue), a distinct feature of the cytokine receptors. This motif is thought to play a major role in correct folding and activation of the receptor. The complex between leptin and the D5CA domain was analyzed using nuclear magnetic resonance spectroscopy and the amino acid residues implicated in the binding were determined. To investigate which parts of the receptor that can adopt alternative conformations and thereby expand the knowledge of the domains that participate in signal transduction, NMR spectra of the D2 and the D5CA domains were recorded under high hydrostatic pressure. Finally, to gain further insight into the role of this motif for the structure of cytokine receptors a series of peptides containing the WSXWS motif were structurally characterized by CD and NMR spectroscopy. The results demonstrate that peptides comprising the WSXWS containing sequences from the leptin receptor and the prolactin receptor have different intrinsic preferences for forming interactions between the aromatic residues of the peptide. It may be speculated that these differences affect the ability of the full domains to form alternative structures around the WSXWS motif.