Role of C-terminal B-chain residues in insulin assembly: the structure of hexameric LysB28ProB29-human insulin

Structure
E CiszakG D Smith

Abstract

LysB28ProB29-human insulin (Humalog), a fully potent insulin analog in which the prolyl, lysyl sequence at the C-terminal end of the B-chain is inverted, exhibits a decreased association of monomers to dimers leading to rapid in vivo absorption. This provides important benefits for the insulin-requiring diabetic. In spite of its monomeric nature, LysB28ProB29-human insulin can exist as a discrete hexameric structure in the presence of both zinc and phenol. Studies of the crystal structure of LysB28ProB29-human insulin in a hexameric complex were initiated to gain a molecular understanding of the effect of the sequence inversion on the analog's self-association properties and, consequently, its in vivo efficacy. Under the conditions reported, LysB28ProB29-human insulin crystallized as a T3Rf3 hexamer that is isomorphous with the uncomplexed T3Rf3 native human insulin hexamer previously known as '4Zn insulin'. The three-dimensional structure of the T3Rf3 hexamer was determined by X-ray crystallographic methods to a resolution of 2.3 A. The prolyl, lysyl sequence inversion leads to local conformational changes at the C termini of the B-chains which eliminate two critical hydrophobic interactions and weaken two terminal beta-sheet ...Continue Reading

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