Importance of Receptor Flexibility in Binding of Cyclam Compounds to the Chemokine Receptor CXCR4
Importance of Receptor Flexibility in Binding of Cyclam Compounds to the Chemokine Receptor CXCR4
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DOI：
10.1021/ci1003027
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发表时间：
2011-01-01
影响因子：
5.6
通讯作者：
Vaidehi, Nagarajan
中科院分区：
文献类型：
--
作者：
Lam, Alfonso R.;Bhattacharya, Supriyo;Vaidehi, Nagarajan
我们已经阐明了四个moncyclam和一个bicyclam拮抗剂AMD 3100，在人类趋化因子受体CXCR 4的结合位点。利用预测的CXCR 4结构模型，我们进一步预测了这些cyclam化合物的结合位点。我们使用的计算方法LITiCon映射的单和双环化合物稳定的受体结构的差异。考虑到受体的灵活性，导致cyclam化合物的单一结合模式，这在以前使用单一受体结构模型和固定受体对接算法是不可能的。monoclam拮抗剂与bicylam拮抗剂相比，稳定的受体构象存在几个显著差异。Cu ~（2+）离子在cyclam化合物中的负载使cyclam环的尺寸缩小，残基D262（6.58）在与monoclam化合物中的铜离子键合中起重要作用，而残基E288（7.39）对于bicyclam化合物是重要的。
We have elucidated the binding sites of four moncyclam and one bicyclam antagonist AMD3100, in the human chemokine receptor CXCR4. Using the predicted structural models of CXCR4, we have further predicted the binding sites of these cyclam compounds. We used the computational method LITiCon to map the differences in receptor structure stabilized by the mono and bicyclam compounds. Accounting for the receptor flexibility lead to a single binding mode for the cyclam compounds, that has not been possible previously using a single receptor structural model and fixed receptor docking algorithms. There are several notable differences in the receptor conformations stabilized by monocyclam antagonist compared to a bicylam antagonist. The loading of the Cu2+ ions in the cyclam compounds, shrinks the size of the cyclam rings and the residue D262(6.58) plays an important role in bonding to the copper ion in the monocylam compounds while residue E288(7.39) is important for the bicyclam compound.