Department of Pediatrics, Division of Endocrinology and Diabetes, Stanford University, Stanford, CA, USA.
Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
Nat Chem Biol. 2022 May;18(5):511-519. doi: 10.1038/s41589-022-00981-0. Epub 2022 Mar 14.
Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions.
芋螺毒液含有多种具有生物活性的肽，包括胰岛素样分子，它们具有独特的结构特征、结合模式和生化特性。在这里，我们报告了一种具有延长 A 链和截断 B 链的活性人源化芋螺毒液胰岛素，并使用低温电子显微镜（cryo-EM）和蛋白质工程来阐明其与人胰岛素受体（IR）外域的相互作用。我们揭示了延长的 A 链如何补偿 B 链残基的缺失，这些残基对于人胰岛素的活性至关重要，但也会通过延迟从皮下注射部位溶解而影响治疗效果。这一发现为开发改良治疗性胰岛素提供了思路。奇怪的是，该受体显示出从对称状态到高度不对称的低丰度结构的连续变化，该结构显示出使用先前表征的位点 1 和位点 2 相互作用的两个元素来协调单个人源化毒液胰岛素的使用。
