The crystal structures of free T-state and R-state glycogen phosphorylase (GP) and of R-state GP in complex with the allosteric activators IMP and AMP are reported at improved resolution. GP is a validated pharmaceutical target for the development of antihyperglycaemic agents, and the reported structures may have a significant impact on structure-based drug-design efforts. Comparisons with previously reported structures at lower resolution reveal the detailed conformation of important structural features in the allosteric transition of GP from the T-state to the R-state. The conformation of the N-terminal segment (residues 7–17), the position of which was not located in previous T-state structures, was revealed to form an α-helix (now termed α0). The conformation of this segment (which contains Ser14, phosphorylation of which leads to the activation of GP) is significantly different between the T-state and the R-state, pointing in opposite directions. In the T-state it is packed between helices α4 and α16 (residues 104–115 and 497–508, respectively), while in the R-state it is packed against helix α1 (residues 22′–38′) and towards the loop connecting helices α4′ and α5′ of the neighbouring subunit. The allosteric binding site where AMP and IMP bind is formed by the ordering of a loop (residues 313–326) which is disordered in the free structure, and adopts a conformation dictated mainly by the type of nucleotide that binds at this site.

中文翻译：

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重新审视糖原磷酸化酶：扩展游离酶以及与变构激活剂复合物的 R 和 T 态结构的分辨率

以更高的分辨率报道了游离 T 态和 R 态糖原磷酸化酶 (GP) 以及与变构激活剂 IMP 和 AMP 复合的 R 态 GP 的晶体结构。GP 是抗高血糖药物开发的经过验证的药物靶标，所报道的结构可能对基于结构的药物设计工作产生重大影响。与先前报道的较低分辨率结构的比较揭示了 GP 从 T 状态到 R 状态的变构转变中重要结构特征的详细构象。N端片段（残基7-17）的构象，其位置在以前的T态结构中不存在，被揭示形成α螺旋（现在称为α0）。该片段（包含 Ser14，其磷酸化导致 GP 激活）的构象在 T 态和 R 态之间显着不同，指向相反的方向。在 T 状态下，它填充在螺旋 α4 和 α16（分别为残基 104-115 和 497-508）之间，而在 R 状态下，它填充在螺旋 α1（残基 22′-38′）和环路之间连接相邻亚基的螺旋α4'和α5'。AMP 和 IMP 结合的变构结合位点是由自由结构中无序的环（残基 313-326）的排序形成的，并采用主要由在此位点结合的核苷酸类型决定的构象。