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首页> 外文期刊>Biochemistry >Altered Enthalpy-Entropy Compensation in Picomolar Transition State Analogues of Human Purine Nucleoside Phosphorylase
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Altered Enthalpy-Entropy Compensation in Picomolar Transition State Analogues of Human Purine Nucleoside Phosphorylase

机译：人嘌呤核苷磷酸化酶的皮摩尔过渡态类似物的改变的焓-熵补偿。

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摘要

Human purine nucleoside phosphorylase (PNP) belongs to the trimeric class of PNPs and isnessential for catabolism of deoxyguanosine. Genetic deficiency of PNP in humans causes a specific T-cellnimmune deficiency, and transition state analogue inhibitors of PNP are in development for treatment of T-cellncancers and autoimmune disorders. Four generations of Immucillins have been developed, each of whichncontains inhibitors binding with picomolar affinity to human PNP. Full inhibition of PNP occurs uponnbinding to the first of three subunits, and binding to subsequent sites occurs with negative cooperativity. Inncontrast, substrate analogue and product bind without cooperativity. Titrations of human PNP usingnisothermal calorimetry indicate that binding of a structurally rigid first-generation Immucillin (Kd =56 pM)nis driven by large negative enthalpy values (ΔH = -21.2 kcal/mol) with a substantial entropic (-TΔS)npenalty. The tightest-binding inhibitors (Kd =5-9 pM) have increased conformational flexibility. Despitentheir conformational freedom in solution, flexible inhibitors bind with high affinity because of reducednentropic penalties. Entropic penalties are proposed to arise from conformational freezing of the PNP3ninhibitorncomplex with the entropy term dominated by protein dynamics. The conformationally flexible Immucillinsnreduce the system entropic penalty. Disrupting the ribosyl 50n-hydroxyl interaction of transition statenanalogues with PNP causes favorable entropy of binding. Tight binding of the 17 Immucillins is characterizednby large enthalpic contributions, emphasizing their similarity to the transition state. Via introduction ofnflexibility into the inhibitor structure, the enthalpy-entropy compensation pattern is altered to permitntighter binding.
机译：人嘌呤核苷磷酸化酶（PNP）属于PNPs的三聚体类，对于脱氧鸟苷的分解代谢是必需的。人类中PNP的遗传缺陷会导致特定的T细胞免疫缺陷，目前正在开发PNP的过渡态类似物抑制剂，以治疗T细胞癌和自身免疫性疾病。已经开发了四代伊莫西林，其中每一代都包含与人PNP具有皮摩尔亲和力的抑制剂。当与三个亚基中的第一个结合时，会完全抑制PNP，而与后续位点的结合则具有负协同作用。 Inncontrast，底物类似物和产物结合而没有协同作用。使用等温量热法滴定人PNP表示，结构刚性的第一代Immucillin（Kd = 56 pM）nis受较大的负焓值（ΔH= -21.2 kcal / mol）驱动，具有很大的熵（-TΔS）罚分。最紧密结合的抑制剂（Kd = 5-9 pM）具有增强的构象柔韧性。尽管它们在溶液中的构象自由度，但是由于减少的熵损失，柔性抑制剂以高亲和力结合。熵的损失被认为是由于PNP3ninhibitorn复合体的构象冻结而引起的，熵的术语由蛋白质动力学决定。构型灵活的免疫抑制剂减少了系统的熵损失。破坏过渡态类似物与PNP的核糖基50n-羟基相互作用会引起良好的结合熵。 17个伊米西林的紧密结合的特征在于焓的贡献很大，强调了它们与过渡态的相似性。通过将柔韧性引入抑制剂结构，焓-熵补偿模式被改变为允许更紧密的结合。

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