Počet záznamů: 1  

Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

  1. 1. 0435229 - UOCHB-X 2015 RIV US eng J - Článek v odborném periodiku
    Žáková, Lenka - Kletvíková, Emília - Lepšík, Martin - Collinsová, Michaela - Watson, C. J. - Turkenburg, J. P. - Jiráček, Jiří - Brzozowski, A. M.
    Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex.
    Acta Crystallographica Section D-Biological Crystallography. Roč. 70, č. 10 (2014), s. 2765-2774 ISSN 0907-4449
    Grant CEP: GA ČR GPP207/11/P430; GA ČR GBP208/12/G016
    Institucionální podpora: RVO:61388963
    Klíčová slova: insulin * insulin receptor * complex * active form * analog * structure
    Kód oboru RIV: CE - Biochemie
    Impakt faktor: 7.232, rok: 2013

    The structural characterization of the insulin-insulin receptor (IR) interaction still lacks the conformation of the crucial B21-B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.
    Trvalý link: http://hdl.handle.net/11104/0239539