Malliavin Thérèse E
Institut Pasteur and CNRS UMR 3528, Unité de Bioinformatique Structurale, 28, rue du Dr Roux, F-75015 Paris, France.
Toxins (Basel). 2017 Jun 26;9(7):199. doi: 10.3390/toxins9070199.
Although CyaA has been studied for over three decades and revealed itself to be a very good prototype for developing various biotechnological applications, only a little is known about its functional dynamics and about the conformational landscape of this protein. Molecular dynamics simulations helped to clarify the view on these points in the following way. First, the model of interaction between AC and calmodulin (CaM) has evolved from an interaction centered on the surface between C-CaM hydrophobic patch and the α helix H of AC, to a more balanced view, in which the C-terminal tail of AC along with the C-CaM Calcium loops play an important role. This role has been confirmed by the reduction of the affinity of AC for calmodulin in the presence of R338, D360 and N347 mutations. In addition, enhanced sampling studies have permitted to propose a representation of the conformational space for the isolated AC. It remains to refine this representation using structural low resolution information measured on the inactive state of AC. Finally, due to a virtual screening study on another adenyl cyclase from , weak inhibitors of AC have been discovered.
尽管百日咳毒素腺苷酸环化酶（CyaA）已被研究了三十多年，并且已证明它是开发各种生物技术应用的非常好的原型，但对于其功能动力学以及该蛋白质的构象景观却知之甚少。分子动力学模拟通过以下方式有助于阐明这些问题。首先，腺苷酸环化酶（AC）与钙调蛋白（CaM）之间的相互作用模型已从以C-CaM疏水补丁与AC的α螺旋H之间的表面为中心的相互作用，演变为一种更加平衡的观点，即AC的C末端尾巴与C-CaM钙环起着重要作用。R338、D360和N347突变存在时AC对钙调蛋白亲和力的降低证实了这一作用。此外，增强采样研究允许提出分离的AC构象空间的表示。仍有待使用在AC非活性状态下测量的结构低分辨率信息来完善这种表示。最后，由于对另一种腺苷酸环化酶的虚拟筛选研究，发现了AC的弱抑制剂。
