Weiss Michael A
Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Vitam Horm. 2009;80:33-49. doi: 10.1016/S0083-6729(08)00602-X.
Crystal structures of insulin are remarkable for a long-range reorganization among three families of hexamers (designated T(6), T(3)R(3)(f), and R(6)). Although these structures are well characterized at atomic resolution, the biological implications of the TR transition remain the subject of speculation. Recent studies indicate that such allostery reflects a structural switch between distinct folding-competent and active conformations. Stereospecific modulation of this switch by corresponding d- and l-amino-acid substitutions yields reciprocal effects on protein stability and receptor-binding activity. Naturally occurring human mutations at the site of conformational change impair the folding of proinsulin and cause permanent neonatal-onset diabetes mellitus. The repertoire of classical structures thus foreshadows the conformational lifecycle of insulin in vivo. By highlighting the richness of information provided by protein crystallography-even in a biological realm far removed from conditions of crystallization-these findings validate the prescient insights of the late D. C. Hodgkin. Future studies of the receptor-bound structure of insulin may enable design of novel agonists for the treatment of diabetes mellitus.
胰岛素的晶体结构在六聚体的三个家族（分别命名为T(6)、T(3)R(3)(f)和R(6)）之间进行远程重组方面表现显著。尽管这些结构在原子分辨率下已得到充分表征，但TR转变的生物学意义仍有待推测。最近的研究表明，这种变构反映了不同的折叠能力构象和活性构象之间的结构转换。通过相应的d-和l-氨基酸取代对这种转换进行立体特异性调节，会对蛋白质稳定性和受体结合活性产生相反的影响。在构象变化位点自然发生的人类突变会损害胰岛素原的折叠，并导致永久性新生儿糖尿病。因此，经典结构的组合预示了胰岛素在体内的构象生命周期。通过强调蛋白质晶体学所提供信息的丰富性——即使是在与结晶条件相差甚远的生物学领域——这些发现证实了已故的D.C.霍奇金的先见之明。未来对胰岛素与受体结合结构的研究可能有助于设计治疗糖尿病的新型激动剂。
