MWC allosteric model explains unusual hemoglobin-oxygen binding curves from sickle cell drug binding.
MWC allosteric model explains unusual hemoglobin-oxygen binding curves from sickle cell drug binding.
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DOI：
10.1016/j.bpj.2021.04.024
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发表时间：
2021-06-15
影响因子：
3.4
通讯作者：
Eaton WA
中科院分区：
文献类型：
--
作者：
Henry ER;Harper J;Glass KE;Metaferia B;Louis JM;Eaton WA
一种氧亲和力修饰药物voxelotor最近被FDA批准用于治疗镰状细胞病。提出的作用机制是通过药物优先结合到R四级构象，其不能与T构象共聚形成镰状纤维。在这里，我们报告了广泛不同的氧解离和氧缔合曲线的存在下，voxelotor的正常血液和解释的结果在变构模型的Monod，怀曼，和Changeux与药物结合。该模型在定量解释一个复杂的数据集，只是增加了药物结合和解离速率的R和T构象。尽管药物从R的缓慢解离导致非时间依赖性解离曲线，但变化的缔合曲线是由于药物从T的缓慢解离以及药物与T的极慢结合。通过计算真实的平衡曲线的模型参数，我们表明，将有一个较小的减少，从左移的药物结合引起的解离曲线，如果药物结合和解离的R和T是快速的氧输送。我们应用Monod、Wyman和Changeux模型再次证明了它在解释血红蛋白的许多不同类型的实验结果方面的巨大力量。它也应该是有助于分析氧结合和在体内传递在未来的调查氧亲和力修饰药物的镰状细胞病。
An oxygen-affinity-modifying drug, voxelotor, has very recently been approved by the FDA for treatment of sickle cell disease. The proposed mechanism of action is by preferential binding of the drug to the R quaternary conformation, which cannot copolymerize with the T conformation to form sickle fibers. Here, we report widely different oxygen dissociation and oxygen association curves for normal blood in the presence of voxelotor and interpret the results in terms of the allosteric model of Monod, Wyman, and Changeux with the addition of drug binding. The model does remarkably well in quantitatively explaining a complex data set with just the addition of drug binding and dissociation rates for the R and T conformations. Whereas slow dissociation of the drug from R results in time-independent dissociation curves, the changing association curves result from slow dissociation of the drug from T, as well as extremely slow binding of the drug to T. By calculating true equilibrium curves from the model parameters, we show that there would be a smaller decrease in oxygen delivery from the left shift in the dissociation curve caused by drug binding if drug binding and dissociation for both R and T were rapid. Our application of the Monod, Wyman, and Changeux model demonstrates once more its enormous power in explaining many different kinds of experimental results for hemoglobin. It should also be helpful in analyzing oxygen binding and in vivo delivery in future investigations of oxygen-affinity-modifying drugs for sickle cell disease.
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影响因子：
6.5
作者：
Abdulmalik, O;Safo, MK;Asakura, T
通讯作者：
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