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首页> 外文期刊>Journal of Molecular Biology >Glycosidic bond conformation preference plays a pivotal role in catalysis of RNA pseudouridylation: a combined simulation and structural study.
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Glycosidic bond conformation preference plays a pivotal role in catalysis of RNA pseudouridylation: a combined simulation and structural study.

机译：糖苷键构象偏好在催化RNA假尿苷化中起关键作用：结合模拟和结构研究。

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摘要

The most abundant chemical modification on RNA is isomerization of uridine (or pseudouridylation) catalyzed by pseudouridine synthases. The catalytic mechanism of this essential process remains largely speculative, partly due to lack of knowledge of the pre-reactive state that is important to the identification of reactive chemical moieties. In the present study, we showed, using orthogonal space random-walk free-energy simulation, that the pre-reactive states of uridine and its reactive derivative 5-fluorouridine, bound to a ribonucleoprotein particle pseudouridine synthase, strongly prefer the syn glycosidic bond conformation, while that of the nonreactive 5-bromouridine-containing substrate is largely populated in the anti conformation state. A high-resolution crystal structure of the 5-bromouridine-containing substrate bound to the ribonucleoprotein particle pseudouridine synthase and enzyme activity assay confirmed the anti nonreactive conformation and provided the molecular basis for its confinement. The observed preference for the syn pre-reactive state by the enzyme-bound uridine may help to distinguish among currently proposed mechanisms.
机译：RNA上最丰富的化学修饰是假尿苷合酶催化的尿苷异构化（或假尿苷化）。该基本过程的催化机理在很大程度上仍是推测性的，部分原因是由于缺乏对反应性化学部分的识别很重要的反应前状态的知识。在本研究中，我们显示了使用正交空间随机游走自由能模拟，与核糖核蛋白颗粒假尿苷合酶结合的尿苷及其反应性衍生物5-氟尿苷的预反应态，强烈偏爱顺糖苷键构象，而非反应性的含5-溴尿苷的底物大部分以反构象状态填充。与核糖核蛋白颗粒假尿苷合酶结合的含5-溴尿苷的底物的高分辨率晶体结构和酶活性测定证实了抗非反应性构象，并为其限定提供了分子基础。通过酶结合的尿苷观察到的对顺式预反应态的偏爱可能有助于区分当前提出的机制。

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