“…However, structural biochemistry of integral membrane proteins in general faces formidable conceptual and technical challenges due to the low concentrations at which they are naturally present in organisms, the difficulty in finding adequate recombinant overexpression systems that yield sufficient amounts of native-like protein, and their insolubility in strictly aqueous media, which requires screening for detergents and lipids that mimic the native membrane environment (35). Consequently, the only IMMP structures published to date are that of the intramembrane site-2 protease (36) from the hyperthermophilic archaeon Methanocaldococcus jannaschii (MEROPS family M50), an ortholog of a human enzyme that releases the N-terminal transcription factor domain from membranebound sterol regulatory element-binding proteins (36 -38) and is unrelated to M48 and M56 IMMPs, and of human and yeast FACE1/Ste24p (Protein Data Bank (PDB) codes 4AW6 and 4IL3 (39,40)), the only functional, truly integral-membrane representatives of families M48 and M56. In such a scenario, strategies aimed at obtaining high resolution structural information on soluble, correctly folded fragments of IMMP target proteins, such as globular catalytic domains (CDs) inserted into the overall transmembrane scaffold, may prove helpful in both the study of catalytic mechanisms and the design of drug-like inhibitors.…”