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Diabetes-Associated Mutations in Insulin Identify Invariant Receptor Contacts

¹ Department of Biochemistry, Case Western Reserve School of Medicine, Cleveland, Ohio
² Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York University, New York, New York
³ Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois

Mutations in human insulin cause an autosomal-dominant syndrome of diabetes and fasting hyperinsulinemia. We demonstrate by residue-specific photo cross-linking that diabetes-associated mutations occur at receptor-binding sites. The studies use para-azido-phenylalanine, introduced at five sites by total protein synthesis. Because two such sites (Val^A3 and Phe^B24) are largely buried in crystal structures of the free hormone, their participation in receptor binding is likely to require a conformational change to expose a hidden functional surface. Our results demonstrate that this surface spans both chains of the insulin molecule and includes sites of rare human mutations that cause diabetes.

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