Abstract
Recent advances in the crystallographic analysis of the insulin receptor and its mode of activation by insulin provide a novel foundation for the design of insulin analogues for the treatment of diabetes mellitus. The structure of the receptor ectodomain, elucidated by M. Lawrence, C. Ward, and their colleagues in Melbourne, Australia, revealed an inverted-V dimer in which the primary insulin-binding site comprises the N-terminal beta-helix of one alpha-subunit and a nascent C-terminal alpha-helix from the other. Contact sites and evidence for bidirectional induced fit have been obtained from cross-linking studies employing synthetic photo-reactive insulin derivatives or biosynthetic photo-reactive receptor variants engineered by expanded genetic-code technology. Such basic advances have enabled translational progress toward the development of ultra-concentrated and rapid-acting insulin analogs designed to address unmet clinical needs of minority populations, including African-American women and indigenous Americans with diabetes complicated by obesity and marked insulin resistance. Together, our biochemical, biophysical, and structural studies illustrate the potential value of basic science to multi-disciplinary approaches to health-care disparities among disadvantaged populations.
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