The crystal structure of the proprotein processing proteinase furin explains its stringent specificity
The crystal structure of the proprotein processing proteinase furin explains its stringent specificity
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DOI：
10.1038/nsb941
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发表时间：
2003-07-01
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影响因子：
--
通讯作者：
Than, ME
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文献类型：
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作者：
Henrich, S;Cameron, A;Than, ME
在真核生物中，许多必需的分泌蛋白质和肽激素被一类钙依赖性内蛋白酶的成员从较大的前体中切除，即蛋白酶-前蛋白转化酶（PC）。弗林蛋白酶是哺乳动物PC家族中最具特征的成员，在胚胎发生和体内平衡中具有重要功能，但也涉及各种病理学，如肿瘤转移、神经变性和由炭疽和致病性埃博拉病毒株等病原体引起的各种细菌和病毒疾病。弗林蛋白酶切割蛋白质前体具有窄的特异性，遵循碱性Arg-Xaa-Lys/Arg-Arg-like基序。癸酰基-Arg-Val-Lys-Arg-氯甲基酮（dec-RVKR-cmk）抑制的小鼠弗林蛋白酶胞外域的2.6埃晶体结构（第一个PC结构）揭示了与催化结构域相关的八链卷曲P结构域。轮廓的表面环形状的活性位点的裂缝，从而解释弗林蛋白酶的严格要求精氨酸在P1和P4，赖氨酸在P2网站的高度电荷互补的口袋。该结构还解释了弗林蛋白酶在P3、P5和P6位点上对碱性残基的偏好。这种结构将有助于抗病毒和抗菌药物的合理设计。
In eukaryotes, many essential secreted proteins and peptide hormones are excised from larger precursors by members of a class of calcium-dependent endoproteinases, the prohormone-proprotein convertases (PCs). Furin, the best-characterized member of the mammalian PC family, has essential functions in embryogenesis and homeostasis but is also implicated in various pathologies such as tumor metastasis, neurodegeneration and various bacterial and viral diseases caused by such pathogens as anthrax and pathogenic Ebola virus strains. Furin cleaves protein precursors with narrow specificity following basic Arg-Xaa-Lys/Arg-Arg-like motifs. The 2.6 Angstrom crystal structure of the decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk) inhibited mouse furin ectodomain, the first PC structure, reveals an eight-stranded jelly-roll P domain associated with the catalytic domain. Contoured surface loops shape the active site by cleft, thus explaining furin's stringent requirement for arginine at P1 and P4, and lysine at P2 sites by highly charge-complementary pockets. The structure also explains furin's preference for basic residues at P3, P5 and P6 sites. This structure will aid in the rational design of antiviral and antibacterial drugs.