Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex.
Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex.
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DOI：
10.1107/s1399004714017775
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发表时间：
2014-10
期刊：
影响因子：
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通讯作者：
Brzozowski AM
中科院分区：
文献类型：
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作者：
Záková L;Kletvíková E;Lepšík M;Collinsová M;Watson CJ;Turkenburg JP;Jiráček J;Brzozowski AM
[AsnB26]-和[GlyB26]-胰岛素突变体在没有化学修饰的情况下获得了类似B26的折叠。它们的结构与胰岛素受体界面相匹配，并扩大了胰岛素构象的光谱。胰岛素-胰岛素受体(IR)相互作用的结构特征仍然缺乏关键的B21-B30胰岛素区域的构象，该区域必须与其存储形式不同，以确保有效的受体结合。在这里，它表明，胰岛素类似物修饰的天然氨基酸在TyrB26位可以代表这种激素的一种活性形式。特别是，[AsnB26]-胰岛素和[GlyB26]-胰岛素获得了不同于所有已知的天然激素结构的B26转角状构象。它还与受体界面相匹配，避免了实质性的立体冲突。这表明胰岛素与IR结合后可能会形成B26转角样构象。此外，AsnB26突变体对受体的主要代谢B亚型具有意想不到的但显著的结合特异性。由于它与激素B链的B26弯曲相关，AsnB26类似物的结构可能为通过胰岛素受体A和B亚型差异胰岛素信号的结构起源提供第一个结构洞察力。
[AsnB26]- and [GlyB26]-insulin mutants attain a B26-turn like fold without assistance of chemical modifications. Their structures match the insulin receptor interface and expand the spectrum of insulin conformations. 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.