Niv Masha Y, Filizola Marta
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY, USA.
Proteins. 2008 May 1;71(2):575-86. doi: 10.1002/prot.21787.
The recently discovered impact of oligomerization on G-protein coupled receptor (GPCR) function further complicates the already challenging goal of unraveling the molecular and dynamic mechanisms of these receptors. To help understand the effect of oligomerization on the dynamics of GPCRs, we have compared the motion of monomeric, dimeric, and tetrameric arrangements of the prototypic GPCR rhodopsin, using an approximate-yet powerful-normal mode analysis (NMA) technique termed elastic network model (ENM). Moreover, we have used ENM to discriminate between putative dynamic mechanisms likely to account for the recently observed conformational rearrangement of the TM4,5-TM4,5 dimerization interface of GPCRs that occurs upon activation. Our results indicate: (1) significant perturbation of the normal modes (NMs) of the rhodopsin monomer upon oligomerization, which is mainly manifested at interfacial regions; (2) increased positive correlation among the transmembrane domains (TMs) and between the extracellular loop (EL) and TM regions of the rhodopsin protomer; (3) highest interresidue positive correlation at the interfaces between protomers; and (4) experimentally testable hypotheses of differential motional changes within different putative oligomeric arrangements.
最近发现的寡聚化对G蛋白偶联受体（GPCR）功能的影响，使阐明这些受体的分子和动力学机制这一原本就具有挑战性的目标变得更加复杂。为了帮助理解寡聚化对GPCR动力学的影响，我们使用了一种名为弹性网络模型（ENM）的近似但强大的正常模式分析（NMA）技术，比较了典型GPCR视紫红质的单体、二聚体和四聚体排列的运动。此外，我们使用ENM来区分可能解释最近观察到的GPCR在激活时TM4,5 - TM4,5二聚化界面构象重排的假定动力学机制。我们的结果表明：（1）寡聚化后视紫红质单体的正常模式（NMs）受到显著扰动，主要表现在界面区域；（2）视紫红质原体的跨膜结构域（TMs）之间以及细胞外环（EL）与TM区域之间的正相关性增加；（3）原体之间的界面处残基间正相关性最高；（4）不同假定寡聚排列内不同运动变化的可实验验证假设。
