Electron Microscope Unit, University of Cape Town, Rondebosch 7701, South Africa.
Structure. 2011 Apr 13;19(4):471-83. doi: 10.1016/j.str.2011.02.001.
Glutamine synthetases are ubiquitous, homo-oligomeric enzymes essential for nitrogen metabolism. Unlike types I and II, which are well described both structurally and functionally, the larger, type IIIs are poorly characterized despite their widespread occurrence. An understanding of the structural basis for this divergence and the implications for design of type-specific inhibitors has, therefore, been impossible. The first crystal structure of a GSIII enzyme, presented here, reveals a conservation of the GS catalytic fold but subtle differences in protein-ligand interactions suggest possible avenues for the design GSIII inhibitors. Despite these similarities, the divergence of the GSIII enzymes can be explained by differences in quaternary structure. Unexpectedly, the two hexameric rings of the GSIII dodecamer associate on the opposite surface relative to types I and II. The diversity of GS quaternary structures revealed here suggests a nonallosteric role for the evolution of the double-ringed architecture seen in all GS enzymes.
谷氨酰胺合成酶是普遍存在的同型寡聚酶，对氮代谢至关重要。与结构和功能均得到很好描述的 I 型和 II 型不同，尽管 III 型广泛存在，但它们的特征却很差。因此，无法理解这种差异的结构基础及其对特定类型抑制剂设计的影响。本文首次呈现了一种 GSIII 酶的晶体结构，揭示了 GS 催化折叠的保守性，但蛋白-配体相互作用的细微差异表明了设计 GSIII 抑制剂的可能途径。尽管存在这些相似之处，但 GSIII 酶的差异可以通过四级结构的差异来解释。出乎意料的是，GSIII 十二聚体的两个六聚体环相对于 I 型和 II 型在相反的表面上结合。这里揭示的 GS 四级结构的多样性表明，在所有 GS 酶中看到的双环结构的进化具有非变构作用。
