Atomic resolution protein allostery from the multi-state structure of a PDZ domain.
Atomic resolution protein allostery from the multi-state structure of a PDZ domain.
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DOI：
10.1038/s41467-022-33687-x
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发表时间：
2022-10-20
影响因子：
16.6
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中科院分区：
文献类型：
--
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最近在溶液NMR方法的进展，允许确定多状态的蛋白质结构，并在原子分辨率的结构和动态相关的蛋白质位点的见解。这在本工作中证明了充分研究的PDZ 2结构域的蛋白质人酪氨酸磷酸酶1 E的蛋白质变构已被预测。使用精确核Overhauser效应（eNOE）方法计算游离形式和与RA-GEF 2肽复合的双态蛋白质结构。在载脂蛋白中，检测到包含几乎60%结构域的变构构象选择步骤，具有“开放”配体欢迎状态和“闭合”状态，其通过改变β-折叠2、α-螺旋2与残基Lys 38和Lys 72的侧链之间的距离来阻碍结合位点。所观察到的诱导的拟合型脱辅基全息结构重排与先前发表的基于进化的分析一致，该分析覆盖了约25%的结构域，仅与开放形式的蛋白质变构部分重叠。这些结构研究突出了结构-动力学景观所引起的PDZ 2结构域的专用高度优化和复杂的动态相互作用的存在。在这份手稿中，作者报告了使用生物NMR的PDZ结构域的准确的多状态蛋白质结构。通过研究蛋白质结构状态，作者报告了原子分辨率的变构途径，验证了先前报告的低分辨率发现，并揭示了变构配体与PDZ结构域结合的结构特征。
Recent methodological advances in solution NMR allow the determination of multi-state protein structures and provide insights into structurally and dynamically correlated protein sites at atomic resolution. This is demonstrated in the present work for the well-studied PDZ2 domain of protein human tyrosine phosphatase 1E for which protein allostery had been predicted. Two-state protein structures were calculated for both the free form and in complex with the RA-GEF2 peptide using the exact nuclear Overhauser effect (eNOE) method. In the apo protein, an allosteric conformational selection step comprising almost 60% of the domain was detected with an “open” ligand welcoming state and a “closed” state that obstructs the binding site by changing the distance between the β-sheet 2, α-helix 2, and sidechains of residues Lys38 and Lys72. The observed induced fit-type apo-holo structural rearrangements are in line with the previously published evolution-based analysis covering ~25% of the domain with only a partial overlap with the protein allostery of the open form. These presented structural studies highlight the presence of a dedicated highly optimized and complex dynamic interplay of the PDZ2 domain owed by the structure-dynamics landscape. In this manuscript the authors report accurate multi-state protein structures of the PDZ domain using biological NMR. By looking into protein structural states, the authors report an allosteric pathway at atomic resolution that validates previously reported low resolution findings and uncovered a structural hallmark of the allosteric ligand binding to the PDZ domain.
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影响因子：
15
作者：
Fenwick RB;Schwieters CD;Vögeli B
通讯作者：
Vögeli B
影响因子：
2.7
作者：
Dalvit, C;Fogliatto, G;Stockman, B
通讯作者：
Stockman, B
影响因子：
2.7
作者：
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通讯作者：
Voegeli, Beat
影响因子：
3.8
作者：
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通讯作者：
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影响因子：
2.9
作者：
Chi, Celestine N.;Bach, Anders;Jemth, Per
通讯作者：
Jemth, Per