蛋白激酶磷酸转移反应的构象依赖性
Conformational Dependence of a Protein Kinase Phosphate Transfer Reaction
摘要：
从蛋白质的反应物构象（RC）和过渡态构象（TC）出发，采用平面波密度泛函理论计算了cAMP依赖的蛋白激酶（PKA）催化的磷酸转移反应的原子运动和能量.在TC中，我们计算出反应物和产物几乎是等能的，具有0.2 eV的势垒;而在RC中，磷酸盐转移超过1.2 eV是不利的，具有更高的势垒。对于TC中的蛋白质，参与反应的运动很小，只有P $_γ$和催化质子移动超过0.5 π。结构的检查表明，在RC中的活性位点裂缝是不完全封闭的，并且在产物状态中磷酸化丝氨酸残基的空间不足。总之，这些观察结果意味着磷酸盐转移反应在蛋白质的特定构象中快速可逆地发生，并且该反应可以通过催化位点中十分之几个碱基的变化来门控。
英文摘要：
Atomic motions and energetics for a phosphate transfer reaction catalyzed by the cAMP-dependent protein kinase (PKA) are calculated by plane-wave density functional theory, starting from structures of proteins crystallized in both the reactant conformation (RC) and the transition-state conformation (TC). In the TC, we calculate that the reactants and products are nearly isoenergetic with a 0.2 eV barrier; while phosphate transfer is unfavorable by over 1.2 eV in the RC, with an even higher barrier. With the protein in the TC, the motions involved in reaction are small, with only P$_γ$ and the catalytic proton moving more than 0.5 Å. Examination of the structures reveals that in the RC the active site cleft is not completely closed and there is insufficient space for the phosphorylated serine residue in the product state. Together, these observations imply that the phosphate transfer reaction occurs rapidly and reversibly in a particular conformation of the protein, and that the reaction can be gated by changes of a few tenths of an Åin the catalytic site.
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