Vaidehi Nagarajan, Grisshammer Reinhard, Tate Christopher G
Division of Immunology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Department of Health and Human Services, Rockville, MD 20852, USA.
Trends Pharmacol Sci. 2016 Jan;37(1):37-46. doi: 10.1016/j.tips.2015.09.005. Epub 2015 Nov 5.
Structures of over 30 different G-protein-coupled receptors (GPCRs) have advanced our understanding of cell signaling and have provided a foundation for structure-guided drug design. This exciting progress has required the development of three complementary methods to facilitate GPCR crystallization, one of which is the thermostabilization of receptors by systematic mutagenesis. However, the reason why a particular mutation, or combination of mutations, stabilizes the receptor is not always evident from a static crystal structure. Molecular dynamics (MD) simulations have been used to identify and estimate the energetic factors that affect thermostability through comparing the dynamics of the thermostabilized receptors with structure-based models of the wild-type receptor. The data indicate that receptors are stabilized through a combination of factors, including an increase in receptor rigidity, a decrease in collective motion, reduced stress at specific residues, and the presence of ordered water molecules. Predicting thermostabilizing mutations computationally represents a major challenge for the field.
30多种不同的G蛋白偶联受体（GPCR）的结构加深了我们对细胞信号传导的理解，并为基于结构的药物设计奠定了基础。这一令人振奋的进展需要开发三种互补方法来促进GPCR结晶，其中一种方法是通过系统诱变使受体热稳定。然而，特定突变或突变组合使受体稳定的原因，从静态晶体结构中并不总是显而易见的。分子动力学（MD）模拟已被用于通过比较热稳定受体与野生型受体的基于结构模型的动力学，来识别和估计影响热稳定性的能量因素。数据表明，受体通过多种因素的组合得以稳定，这些因素包括受体刚性增加、集体运动减少、特定残基处的应力降低以及有序水分子的存在。通过计算预测热稳定突变是该领域的一项重大挑战。
