实验小组由加拿大蛋白质工程教授Peter Davies领导，他表示：“这真是令人激动，因为这种蛋白质的结构，以及它的抑制剂如何在不损害自身的前提下阻止其活性，一直以来都难以捉摸。”
在细胞生长和运动所需的重塑蛋白中，人体细胞使用钙蛋白酶(Calpain)来帮助其与其他蛋白质分离。钙离子浓度的异常增高可激活钙蛋白酶。而在心脏病发作和中风时，细胞的血液供应中断，当再度供血时，大量涌入的血液使得细胞内钙离子达到危险的浓度，使钙蛋白酶活性增强，结果给组织造成了很大伤害。研究小组成员Rob Campbell表示：“人们不希望酶的激活或关闭完全不受控制。”
研究还显示了当钙蛋白酶被钙离子激活后，另一种蛋白质——钙蛋白酶抑制蛋白（calpastatin）如何阻止了钙蛋白酶的活性。Campbell和博士生Rachel Hanna能够确定钙绑定的钙蛋白酶的结构，并发现了钙蛋白酶抑制蛋白如何在不受破坏的同时抑制钙蛋白酶。这将有助于设计新药物，防止过度激活的钙蛋白酶对组织造成破坏。（www.ibioo.com）
原始出处：
Nature，456, 409-412，Rachel A. Hanna，Peter L. Davies
Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin
Rachel A. Hanna1, Robert L. Campbell1 & Peter L. Davies1
1 Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6
Calpains are non-lysosomal calcium-dependent cysteine proteinases that selectively cleave proteins in response to calcium signals1 and thereby control cellular functions such as cytoskeletal remodelling, cell cycle progression, gene expression and apoptotic cell death2, 3, 4. In mammals, the two best-characterized members of the calpain family, calpain 1 and calpain 2 (-calpain and m-calpain, respectively), are ubiquitously expressed. The activity of calpains is tightly controlled by the endogenous inhibitor calpastatin, which is an intrinsically unstructured protein capable of reversibly binding and inhibiting four molecules of calpain, but only in the presence of calcium5, 6. To date, the mechanism of inhibition by calpastatin and the basis for its absolute specificity have remained speculative7, 8, 9. It was not clear how this unstructured protein inhibits calpains without being cleaved itself, nor was it known how calcium induced changes that facilitated the binding of calpastatin to calpain. Here we report the 2.4-?-resolution crystal structure of the calcium-bound calpain 2 heterodimer bound by one of the four inhibitory domains of calpastatin. Calpastatin is seen to inhibit calpain by occupying both sides of the active site cleft. Although the inhibitor passes through the active site cleft it escapes cleavage in a novel manner by looping out and around the active site cysteine. The inhibitory domain of calpastatin recognizes multiple lower affinity sites present only in the calcium-bound form of the enzyme, resulting in an interaction that is tight, specific and calcium dependent. This crystal structure, and that of a related complex10, also reveal the conformational changes that calpain undergoes on binding calcium, which include opening of the active site cleft and movement of the domains relative to each other to produce a more compact enzyme.
