Rana Soumendra, Sahoo Amita Rani, Majhi Bharat Kumar
Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar, Odisha 751007, India.
Mol Biosyst. 2016 Apr 26;12(5):1586-99. doi: 10.1039/c6mb00031b.
The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. The study attempts to understand the pharmacology at the "orthosteric" site2 of C5aR rationally by generating a highly refined full-blown model structure of C5aR through advanced molecular modeling techniques, and further subjecting it to automated docking and molecular dynamics (MD) studies in the POPC bilayer. The first series of structural complexes of C5aR respectively bound to a linear native peptide agonist ((h)C5a-CT), a small molecule inverse agonist (NDT) and a cyclic peptide antagonist (PMX53) are reported, apparently establishing the unique pharmacological landscape of the "orthosteric" site2, which also illustrates an energetically distinct but coherent competitive chemistry ("cation-π" vs. "π-π" interactions) involved in distinguishing the established ligands known for targeting the "orthosteric" site2 of C5aR. Over a total of 1 μs molecular dynamics (MD) simulation in the POPC bilayer, it is evidenced that while the agonist prefers a "cation-π" interaction, the inverse agonist prefers a "cogwheel/L-shaped" interaction in contrast to the "edge-to-face/T-shaped" type π-π interactions demonstrated by the antagonist by engaging the F275(7.28) of the C5aR. In the absence of a NMR or crystallographically guided model structure of C5aR, the computational model complexes not only provide valuable insights for understanding the C5aR pharmacology, but also emerge as a promising platform for the design and discovery of future potential drug candidates targeting the (h)C5a-C5aR signaling axes.
C5a受体（C5aR）是一种在药理学上具有重要意义的G蛋白偶联受体（GPCR），它通过在双位点结合模型中募集C5aR上的“正构”位点（N端的位点1和细胞外表面ECS的位点2）与（人）C5a相互作用。然而，C5aR在“正构”位点1或功能上重要的“正构”位点2处复杂的药理学情况以及独特的化学作用仍不清楚，这极大地限制了对C5aR药理学的理解。主要瓶颈之一是缺乏具有适当定义活性位点的C5aR实验结构或精细模型结构。该研究试图通过先进的分子建模技术生成高度精细的C5aR全尺寸模型结构，并进一步在POPC双层中对其进行自动对接和分子动力学（MD）研究，从而合理地了解C5aR在“正构”位点2处的药理学。报道了C5aR分别与线性天然肽激动剂（（人）C5a-CT）、小分子反向激动剂（NDT）和环肽拮抗剂（PMX53）结合的第一系列结构复合物，显然确立了“正构”位点2独特的药理学情况，这也说明了在区分已知靶向C5aR“正构”位点2的既定配体时涉及的能量上不同但连贯的竞争化学（“阳离子-π”与“π-π”相互作用）。在POPC双层中总共超过1微秒的分子动力学（MD）模拟表明，虽然激动剂倾向于“阳离子-π”相互作用，但反向激动剂倾向于“齿轮/ L形”相互作用，这与拮抗剂通过与C5aR的F275（7.28）结合所展示的“边对面/ T形”π-π相互作用形成对比。在缺乏C5aR的NMR或晶体学指导模型结构的情况下，计算模型复合物不仅为理解C5aR药理学提供了有价值的见解，而且还成为设计和发现未来靶向（人）C5a-C5aR信号轴的潜在药物候选物的有前景的平台。
