A substrate-driven allosteric switch that enhances PDI catalytic activity.
A substrate-driven allosteric switch that enhances PDI catalytic activity.
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DOI：
10.1038/ncomms12579
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发表时间：
2016-08-30
影响因子：
16.6
通讯作者：
Flaumenhaft, Robert
中科院分区：
文献类型：
--
作者：
Bekendam, Roelof H.;Bendapudi, Pavan K.;Lin, Lin;Nag, Partha P.;Pu, Jun;Kennedy, Daniel R.;Feldenzer, Alexandra;Chiu, Joyce;Cook, Kristina M.;Furie, Bruce;Huang, Mingdong;Hogg, Philip J.;Flaumenhaft, Robert
蛋白质二硫键异构酶(PDI)是内质网折叠蛋白质所必需的氧化还原酶。PDI的结构域结构是a-b-b‘-x-a’，其中类硫氧还蛋白a和a‘结构域介导二硫键洗牌，b和b’结构域是底物结合。B‘和a’结构域通过x-接头连接，x-接头是一种由19个氨基酸组成的柔性多肽。在这里，我们识别了一类化合物，称为bepristats，目标是b‘的底物结合口袋。在体内，比普利司他可逆地阻断底物结合并抑制血小板聚集和血栓形成。底物结合口袋被Beprstats连接，矛盾地通过取代x-接头来增强a和a‘的催化活性，x-接头起到变构开关的作用，增强催化域中的还原酶活性。这种底物驱动的变构开关也被多肽和蛋白质激活，并存在于其他硫醇异构酶中。我们的结果证明了底物与硫醇异构酶结合增强远端结构域催化活性的机制。蛋白质二硫键异构酶(PDI)是一种具有不同底物结合区和催化区的前血栓形成的多结构域酶。在这里，作者确定了一类新的化合物，这些化合物以PDI底物结合部位为靶点，诱导催化区域的构象变化，抑制血栓形成。
Protein disulfide isomerase (PDI) is an oxidoreductase essential for folding proteins in the endoplasmic reticulum. The domain structure of PDI is a–b–b′–x–a′, wherein the thioredoxin-like a and a′ domains mediate disulfide bond shuffling and b and b′ domains are substrate binding. The b′ and a′ domains are connected via the x-linker, a 19-amino-acid flexible peptide. Here we identify a class of compounds, termed bepristats, that target the substrate-binding pocket of b′. Bepristats reversibly block substrate binding and inhibit platelet aggregation and thrombus formation in vivo. Ligation of the substrate-binding pocket by bepristats paradoxically enhances catalytic activity of a and a′ by displacing the x-linker, which acts as an allosteric switch to augment reductase activity in the catalytic domains. This substrate-driven allosteric switch is also activated by peptides and proteins and is present in other thiol isomerases. Our results demonstrate a mechanism whereby binding of a substrate to thiol isomerases enhances catalytic activity of remote domains. Protein Disulfide Isomerase (PDI) is a prothrombotic, multidomain enzyme with separate substrate binding and catalytic domains. Here, the authors identify a new class of compounds that target the PDI substrate binding site, inducing a conformational change in the catalytic domains and inhibiting thrombosis.
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影响因子：
20.1
作者：
Furie B;Flaumenhaft R
通讯作者：
Flaumenhaft R
DOI：
10.1161/atvbaha.114.303410
发表时间：
2015-01
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Flaumenhaft R;Furie B;Zwicker JI
通讯作者：
Zwicker JI
影响因子：
4.8
作者：
Gallina, A;Hanley, TM;Ryser, HJP
通讯作者：
Ryser, HJP
影响因子：
20.3
作者：
Kim, Kyungho;Hahm, Eunsil;Cho, Jaehyung
通讯作者：
Cho, Jaehyung
影响因子：
4.2
作者：
Dockendorff, Chris;Aisiku, Omozuanvbo;VerPlank, Lynn;Dilks, James R.;Smith, Daniel A.;Gunnink, Susanna F.;Dowal, Louisa;Negri, Joseph;Palmer, Michelle;MacPherson, Lawrence;Schreiber, Stuart L.;Flaumenhaft, Robert
通讯作者：
Flaumenhaft, Robert