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- W2890416452 startingPage "51" @default.
- W2890416452 abstract "The classical crystal structure of insulin was determined in 1969 by D.C. Hodgkin et al. following a 35-year program of research. This structure depicted a hexamer remarkable for its self-assembly as a zinc-coordinated trimer of dimer. Prominent at the dimer interface was an aromatic triplet of conserved residues at consecutive positions in the B chain: PheB24 , PheB25 and TyrB26 . The elegance of this interface inspired the Oxford team to poetry: A thing of beauty is a joy forever (John Keats as quoted by Blundell, T.L., et al. Advances in Protein Chemistry 26:279-286 [1972]). Here, we revisit this aromatic triplet in light of recent advances in the structural biology of insulin bound as a monomer to fragments of the insulin receptor. Such co-crystal structures have defined how these side chains pack at the primary hormone-binding surface of the receptor ectodomain. On receptor binding, the B-chain β-strand (residues B24-B28) containing the aromatic triplet detaches from the α-helical core of the hormone. Whereas TyrB26 lies at the periphery of the receptor interface and may functionally be replaced by a diverse set of substitutions, PheB24 and PheB25 engage invariant elements of receptor domains L1 and αCT. These critical contacts were anticipated by the discovery of diabetes-associated mutations at these positions by Donald Steiner et al. at the University of Chicago. Conservation of PheB24 , PheB25 and TyrB26 among vertebrate insulins reflects the striking confluence of structure-based evolutionary constraints: foldability, protective self-assembly and hormonal activity." @default.
- W2890416452 created "2018-09-27" @default.
- W2890416452 creator A5075334756 @default.
- W2890416452 creator A5076264613 @default.
- W2890416452 date "2018-09-01" @default.
- W2890416452 modified "2023-10-12" @default.
- W2890416452 title "A thing of beauty: Structure and function of insulin's “aromatic triplet”" @default.
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