APHP, Hôpital Lariboisière, Service de Biochimie et de Biologie Moléculaire, Paris, France.
PLoS One. 2011;6(10):e26245. doi: 10.1371/journal.pone.0026245. Epub 2011 Oct 27.
The diagnostic of orphan genetic disease is often a puzzling task as less attention is paid to the elucidation of the pathophysiology of these rare disorders at the molecular level. We present here a multidisciplinary approach using molecular modeling tools and surface plasmonic resonance to study the function of the ATP7B protein, which is impaired in the Wilson disease. Experimentally validated in silico models allow the elucidation in the Nucleotide binding domain (N-domain) of the Mg(2+)-ATP coordination site and answer to the controversial role of the Mg(2+) ion in the nucleotide binding process. The analysis of protein motions revealed a substantial effect on a long flexible loop branched to the N-domain protein core. We demonstrated the capacity of the loop to disrupt the interaction between Mg(2+)-ATP complex and the N-domain and propose a role for this loop in the allosteric regulation of the nucleotide binding process.
遗传性孤儿病的诊断常常是一项令人费解的任务，因为人们对这些罕见疾病的分子水平病理生理学的认识较少。在这里，我们提出了一种使用分子建模工具和表面等离子体共振的多学科方法来研究 ATP7B 蛋白的功能，该蛋白在威尔逊病中受到损害。经过实验验证的计算模型允许阐明核苷酸结合域（N 域）中的 Mg2+-ATP 配位位点，并回答了 Mg2+离子在核苷酸结合过程中的争议作用。对蛋白质运动的分析表明，它对分支到 N 域蛋白核心的长柔性环有很大的影响。我们证明了该环能够破坏 Mg2+-ATP 复合物与 N 域之间的相互作用，并提出该环在核苷酸结合过程的变构调节中起作用。
