CRYSTAL-STRUCTURE OF A PROLONGED-ACTING INSULIN WITH ALBUMIN-BINDING PROPERTIES

The fatty acid acylated insulin, Lys(B29)-tetradecanoyl, des-(B30) hum an insulin, has been crystallized and the structure determined by X-ra y crystallography. The fatty acid substituent on residue B29 Lys binds reversibly to circulating albumin protein in vivo, and by this mechan ism the hormone's action is prolonged. Crystals of the fatty acid insu lin grow in space group R3, with two dimers in the asymmetric unit, an d diffract to 1.8 Angstrom spacing. The structure has been solved by m olecular replacement and refined using a maximum likelihood method. Th e crystal structure consists of R6 zinc insulin hexamers which contain phenol. The fatty acids can be seen bound between the hexamers, makin g specific interactions with the side chains of residue B1 Phe; howeve r, the lysine side chains to which the fatty acids are covalently atta ched are mostly disordered. The mode of binding of the fatty acids app ears to be determined by crystal packing, and whether or not they inte ract with the protein in this way in solution remains uncertain.