Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
J Struct Biol. 2018 Oct;204(1):19-25. doi: 10.1016/j.jsb.2018.06.004. Epub 2018 Jun 12.
Neprilysin is a transmembrane M13 zinc metalloprotease responsible for the degradation of several biologically active peptides including insulin, enkephalin, substance P, bradykinin, endothelin-1, neurotensin and amyloid-β. The protein has received attention for its role in modulating blood pressure responses with its inhibition producing an antihypertensive response. To date, several inhibitor bound crystal structures of the human neprilysin extracellular domain have been determined, but, a structure free of bound inhibitor or substrate has yet to be reported. Here, we report the first crystal structure free of substrate or inhibitor for the extracellular catalytic domain of human neprilysin at 1.9 Å resolution. This structure will provide a reference point for comparisons to future inhibitor or substrate bound structures. The neprilysin structure also reveals that a closed protein conformation can be adopted in protein crystals absent of bound substrate or inhibitor.
Neprilysin 是一种跨膜 M13 锌金属蛋白酶，负责降解包括胰岛素、脑啡肽、P 物质、缓激肽、内皮素-1、神经降压素和淀粉样-β在内的几种生物活性肽。该蛋白因其在调节血压反应中的作用而受到关注，其抑制作用产生抗高血压反应。迄今为止，已经确定了几种人肾素酶外肽酶结构域的抑制剂结合晶体结构，但尚未报道无结合抑制剂或底物的结构。在这里，我们报道了第一个 1.9 Å 分辨率的无底物或抑制剂的人肾素酶外肽酶催化结构域的晶体结构。该结构将为未来与抑制剂或底物结合结构的比较提供参考点。肾素酶的结构还表明，在没有结合底物或抑制剂的情况下，蛋白质晶体可以采用封闭的蛋白质构象。
