Departments of Molecular Medicine and Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Acta Crystallogr D Struct Biol. 2019 Mar 1;75(Pt 3):325-332. doi: 10.1107/S2059798319000809. Epub 2019 Feb 28.
The clostripain-like (C11) family of cysteine proteases are ubiquitously produced by the vast majority of the bacterial strains that make up the human distal gut microbiome. Recent reports show that some C11 proteases promote host immune responses and bacterial pathogenesis, including the induction of neutrophil phagocytosis and the activation of bacterial pathogenic toxins, respectively. The crystal structure of distapain, the only C11 protease predicted within the genome of the commensal bacterium Parabacteroides distasonis, was determined in the inactive zymogen state to 1.65 Å resolution. This is the first C11 protease structure of a zymogen, and the structure helped to uncover key unique conformations among critical active-site residues that are likely to assist in preserving the inactive protease. His135, a member of the catalytic dyad, is repositioned approximately 5.5 Å from the orientation found in active C11 structures and forms a hydrogen bond to Asp180 and a π-stacking interaction with Trp133. The structure sheds light on the potential importance of Asp180 and Trp133, as these residues are highly conserved across C11 proteases. Structure elucidation of C11 proteases will ultimately help to identify new ways to chemically and/or biologically regulate this family of enzymes, which represent potential drug-discovery targets in microbiome-related gastrointestinal diseases.
Clostripain 样（C11）家族的半胱氨酸蛋白酶广泛存在于构成人类远端肠道微生物组的绝大多数细菌菌株中。最近的报告表明，一些 C11 蛋白酶促进宿主免疫反应和细菌发病机制，分别包括诱导中性粒细胞吞噬作用和激活细菌致病毒素。共生菌 Parabacteroides distasonis 基因组中唯一预测的 C11 蛋白酶 distapain 的晶体结构以无活性酶原状态确定，分辨率为 1.65 Å。这是第一个 C11 蛋白酶原的结构，该结构有助于揭示关键活性位点残基之间的独特构象，这些构象可能有助于保持无活性蛋白酶。催化二联体的成员 His135 从活性 C11 结构中发现的取向重新定位约 5.5 Å，并与 Asp180 形成氢键和与 Trp133 形成π堆积相互作用。该结构阐明了 Asp180 和 Trp133 的潜在重要性，因为这些残基在 C11 蛋白酶中高度保守。C11 蛋白酶的结构阐明最终将有助于确定化学和/或生物调节该酶家族的新方法，这是与微生物组相关的胃肠道疾病中潜在的药物发现靶点。
