Serine racemase (SR) is a pyridoxal 5′‐phosphate (PLP)‐containing enzyme that converts l‐serine to d‐serine, an endogenous co‐agonist for the N‐methyl‐d‐aspartate receptor (NMDAR) subtype of glutamate ion channels. SR regulates d‐serine levels by the reversible racemization of l‐serine to d‐serine, as well as the catabolism of serine by α,β‐elimination to produce pyruvate. The modulation of SR activity is therefore an attractive therapeutic approach to disorders associated with abnormal glutamatergic signalling since it allows an indirect modulation of NMDAR function. In the present study, a 1.89 Å resolution crystal structure of the human SR holoenzyme (including the PLP cofactor) with four subunits in the asymmetric unit is described. Comparison of this new structure with the crystal structure of human SR with malonate (PDB entry 3l6b) shows an interdomain cleft that is open in the holo structure but which disappears when the inhibitor malonate binds and is enclosed. This is owing to a shift of the small domain (residues 78–155) in human SR similar to that previously described for the rat enzyme. This domain movement is accompanied by changes within the twist of the central four‐stranded β‐sheet of the small domain, including changes in the ϕ–ψ angles of all three residues in the C‐terminal β‐strand (residues 149–151). In the malonate‐bound structure, Ser84 (a catalytic residue) points its side chain at the malonate and is preceded by a six‐residue β‐strand (residues 78–83), but in the holoenzyme the β‐strand is only four residues (78–81) and His82 has ϕ–ψ values in the α‐helical region of the Ramachandran plot. These data therefore represent a crystallographic platform that enables the structure‐guided design of small‐molecule modulators for this important but to date undrugged target.

中文翻译：

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人丝氨酸消旋酶小域内的构象灵活性。

丝氨酸消旋酶 (SR) 是一种含有吡哆醛 5'-磷酸 (PLP) 的酶，可将L-丝氨酸转化为d-丝氨酸，D-丝氨酸是谷氨酸离子N-甲基-d-天冬氨酸受体 (NMDAR) 亚型的内源性共激动剂渠道。SR通过L-丝氨酸可逆外消旋化为d-丝氨酸，以及通过 α,β-消除丝氨酸的分解代谢产生丙酮酸来调节d-丝氨酸水平。因此，SR 活性的调节是治疗与谷氨酸能信号异常相关的疾病的一种有吸引力的治疗方法，因为它允许间接调节 NMDAR 功能。在本研究中，描述了人类 SR 全酶（包括 PLP 辅因子）的 1.89 Å 分辨率晶体结构，其不对称单元中有四个亚基。这种新结构与人 SR 与丙二酸的晶体结构（PDB 条目 3l6b）的比较显示，全结构中存在一个域间裂缝，该裂缝在全息结构中开放，但当抑制剂丙二酸结合并被封闭时，该裂缝消失。这是由于人类 SR 中的小结构域（残基 78-155）发生了变化，类似于之前描述的大鼠酶。该结构域移动伴随着小结构域中央四链 β 片层扭转的变化，包括 C 末端 β 链中所有三个残基（残基 149-151）的 ψ-ψ 角的变化。 。在丙二酸结合结构中，Ser84（催化残基）将其侧链指向丙二酸，前面有一个六残基的β链（残基78-83），但在全酶中，β链只有四个残基(78-81) 和 His82 在 Ramachandran 图的 α 螺旋区域具有 ψ–ψ 值。因此，这些数据代表了一个晶体学平台，可以针对这一重要但迄今为止尚未药物化的目标进行小分子调节剂的结构引导设计。