Computational Biomedicine, Institute for Advanced Simulations IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, Jülich, Germany; Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Computational Biomedicine, Institute for Advanced Simulations IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, Jülich, Germany; Department of Biotechnology, University of Verona, Verona, Italy.
Curr Opin Struct Biol. 2019 Apr;55:8-16. doi: 10.1016/j.sbi.2019.02.009. Epub 2019 Mar 29.
Recently, molecular dynamics simulations, from all atom and coarse grained to hybrid methods bridging the two scales, have provided exciting functional insights into class F (Frizzled and Taste2) GPCRs (about 40 members in humans). Findings include: (i) The activation of one member of the Frizzled receptors (FZD4) involves a bending of transmembrane helix TM7 far larger than that in class A GPCRs. (ii) The affinity of an anticancer drug targeting another member (Smoothened receptor) decreases in a specific drug-resistant variant, because the mutation ultimately disrupts the binding cavity and affects TM6. (iii) A novel two-state recognition mechanism explains the very large agonist diversity for at least one member of the Taste2 GPCRs, hTAS2R46.
最近，从全原子和粗粒到混合方法的分子动力学模拟，在两个尺度之间架起了桥梁，为 F 类（Frizzled 和 Taste2）GPCR （人类约有 40 个成员）提供了令人兴奋的功能见解。研究结果包括：（i）Frizzled 受体（FZD4）的一种成员的激活涉及跨膜螺旋 TM7 的弯曲程度远大于 A 类 GPCR 的弯曲程度。（ii）针对另一种成员（Smoothened 受体）的抗癌药物的亲和力在特定的耐药变体中降低，因为该突变最终破坏了结合腔并影响 TM6。（iii）一种新的两态识别机制解释了至少一种 Taste2 GPCR（hTAS2R46）的非常大的激动剂多样性。
