Sandal Massimo, Behrens Maik, Brockhoff Anne, Musiani Francesco, Giorgetti Alejandro, Carloni Paolo, Meyerhof Wolfgang
Computational Biophysics, German Research School for Simulation Sciences , 52425 Jülich, Germany.
Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) , Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
J Chem Theory Comput. 2015 Sep 8;11(9):4439-49. doi: 10.1021/acs.jctc.5b00472. Epub 2015 Aug 24.
Most human G protein coupled receptors (GPCRs) are activated by small molecules binding to their 7-transmembrane (7-TM) helix bundle. They belong to basally diverging branches: the 25 bitter taste 2 receptors and most members of the very large rhodopsin-like/class A GPCRs subfamily. Some members of the class A branch have been suggested to feature not only an orthosteric agonist-binding site but also a more extracellular or "vestibular" site, involved in the binding process. Here we use a hybrid molecular mechanics/coarse-grained (MM/CG) molecular dynamics approach on a widely studied bitter taste receptor (TAS2R46) receptor in complex with its agonist strychnine. Three ∼1 μs molecular simulation trajectories find two sites hosting the agonist, which together elucidate experimental data measured previously and in this work. This mechanism shares similarities with the one suggested for the evolutionarily distant class A GPCRs. It might be instrumental for the remarkably broad but specific spectrum of agonists of these chemosensory receptors.
大多数人类G蛋白偶联受体（GPCRs）是通过与它们的7次跨膜（7-TM）螺旋束结合的小分子激活的。它们属于基部发散分支：25种苦味受体2以及非常大的视紫红质样/A类GPCRs亚家族的大多数成员。有人提出，A类分支的一些成员不仅具有一个正构激动剂结合位点，还具有一个更靠近细胞外或“前庭”的位点，参与结合过程。在这里，我们对一个广泛研究的苦味受体（TAS2R46）与其激动剂士的宁的复合物采用了混合分子力学/粗粒度（MM/CG）分子动力学方法。三条约1微秒的分子模拟轨迹发现了两个容纳激动剂的位点，这共同解释了之前和这项工作中测量的实验数据。这种机制与为进化上距离较远的A类GPCRs所提出的机制有相似之处。它可能有助于这些化学感应受体的激动剂具有非常广泛但特定的光谱。
