Tyrosine 121 moves revealing a druggable pocket that couples catalysis to ATP-binding in serine racemase
Tyrosine 121 moves revealing a druggable pocket that couples catalysis to ATP-binding in serine racemase
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酪氨酸 121 移动揭示了一个可成药的口袋，该口袋将催化与丝氨酸消旋酶中的 ATP 结合偶联
DOI：
10.1101/2021.02.12.430960
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Koulouris C
中科院分区：
文献类型：
--
作者：
Koulouris C
人丝氨酸消旋酶催化L-丝氨酸外消旋为D-丝氨酸，D-丝氨酸是NMDA型谷氨酸受体的共同激动剂，在突触可塑性、学习和记忆中起重要作用。在含有变构激活剂ATP的闭合HSR结构中，抑制剂丙二酸被封闭在大小结构域之间，而ATP位于活性部位的远端，位于二聚体界面上，与ATPa-磷酸接触的Tyr121羟基。相反，在“开放”的HSR结构中，Tyr121位于小域的核心，其羟基与关键的催化残基Ser84接触。通过将Tyr121从小结构域的核心翻转到二聚体界面来调节SR活性的能力似乎已经在具有CNS的动物身上进化。多个X射线结晶学酶片段结构表明，Tyr121从口袋里翻了出来，这表明这个口袋是可以下药的。
Human serine racemase (hSR) catalyses racemisation of L-serine to D-serine, the latter of which is a co-agonist of the NMDA subtype of glutamate receptors that are important in synaptic plasticity, learning and memory. In a ‘closed’ hSR structure containing the allosteric activator ATP, the inhibitor malonate is enclosed between the large and small domains while ATP is distal to the active site, residing at the dimer interface with the Tyr121 hydroxyl group contacting the ATP a-phosphate. In contrast, in ‘open’ hSR structures, Tyr121 sits in the core of the small domain with its hydroxyl contacting the key catalytic residue Ser84. The ability to regulate SR activity by flipping Tyr121 from the core of the small domain to the dimer interface appears to have evolved in animals with a CNS. Multiple X-ray crystallographic enzymefragment structures show that Tyr121 is flipped out of its pocket, suggesting that this pocket is druggable.