Enzyme Inhibition by Allosteric Capture of an Inactive Conformation
Enzyme Inhibition by Allosteric Capture of an Inactive Conformation
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DOI：
10.1016/j.jmb.2011.06.032
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发表时间：
2011-09-02
影响因子：
5.6
通讯作者：
Craik, Charles S.
中科院分区：
文献类型：
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作者：
Lee, Gregory M.;Shahian, Tina;Craik, Charles S.
人类疱疹病毒蛋白酶 (HEW Pr) 家族的所有成员在弱缔合二聚体时均具有活性，但在单体时则无活性。卡波西肉瘤相关疱疹病毒蛋白酶 (KSHV Pr) 的小分子变构抑制剂将该酶捕获在非活性单体状态，其中 C 端螺旋展开且疏水二聚体界面暴露。 NMR 滴定研究表明，该抑制剂以低微摩尔亲和力与 KSHV Pr 单体结合。 C 端截短的 KSHV Pr 抑制剂复合物的 2.0 埃分辨率 X 射线晶体结构将结合袋定位在二聚体界面处，并在距离变构位点 15 埃的活性位点处显示出显着的构象扰动。 NMR 和 CD 数据表明该小分子通过类似的机制抑制人巨细胞病毒蛋白酶。由于所有 HHV Pr 在功能和结构上都是同源的，因此该抑制剂代表了一类可以开发成广谱治疗药物的化合物，通过破坏蛋白质-蛋白质相互作用来变构调节酶活性。 (C) 2011 Elsevier Ltd. 保留所有权利。
All members of the human herpesvirus protease (HEW Pr) family are active as weakly associating dimers but inactive as monomers. A small-molecule allosteric inhibitor of Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr) traps the enzyme in an inactive monomeric state where the C-terminal helices are unfolded and the hydrophobic dimer interface is exposed. NMR titration studies demonstrate that the inhibitor binds to KSHV Pr monomers with low micromolar affinity. A 2.0-angstrom-resolution X-ray crystal structure of a C-terminal truncated KSHV Pr-inhibitor complex locates the binding pocket at the dimer interface and displays significant conformational perturbations at the active site, 15 angstrom from the allosteric site. NMR and CD data suggest that the small molecule inhibits human cytomegalovirus protease via a similar mechanism. As all HHV Prs are functionally and structurally homologous, the inhibitor represents a class of compounds that may be developed into broad-spectrum therapeutics that allosterically regulate enzymatic activity by disrupting protein-protein interactions. (C) 2011 Elsevier Ltd. All rights reserved.