We previously reported a tethered fusion protein approach to engineer the CLR:RAMP1 and CLR:RAMP2 ECD complexes for crystallization (Moad and Pioszak, 2013), inspired by previous successes using maltose binding protein (MBP) as a “crystallization module” for class B GPCR ECDs (Kumar et al., 2011; Pal et al., 2010; Pioszak et al., 2008, 2009, 2010; Pioszak and Xu, 2008). MBP-RAMP1 or MBP-RAMP2 ECD-CLR ECD fusion proteins in which the two ECDs were covalently tethered with a flexible (Gly-Ser)5 linker were designed to ensure complex stability and enforce 1:1 CLR:RAMP stoichiometry. The tethered RAMP1-CLR ECD fusion was a monomer, whereas the tethered RAMP2-CLR ECD fusion purified as a dimer, but the physiological relevance of oligomerization is unknown. Both proteins selectively bound their respective peptides but failed to yield crystals in the presence of peptides.