Yikun Chen, Kangcheng Song, Wenjun Guo, Miao Wei, Lei Chen
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引用次数: 0
Abstract
The natural product (-)-Englerin A (EA) selectively inhibits renal cancer cell growth by potently activating TRPC4 and TRPC5-containing ion channels. However, its binding site on these channels has remained elusive. In this study, we present two cryo-EM structures of human TRPC5 in complex with EA at 2.5 and 2.6 Å resolution, which reveal the EA-binding site and identify two major conformations influenced by calcium. EA binds between the pore helix and S5/S6 helices of hTRPC5, forming critical hydrophobic and polar interactions that underscore its specificity. Calcium binding at the intracellular domain of TRPC5 induces structural changes that stabilize the domain in a compact conformation. These findings expand our understanding of the structural pharmacology of TRPC5 and provide a framework for investigating calcium regulation in TRPC channels.
天然产物(-)- englerin A （EA）通过有效激活TRPC4和含trpc5离子通道，选择性抑制肾癌细胞生长。然而，其在这些通道上的结合位点仍然难以捉摸。在这项研究中，我们在2.5和2.6 Å分辨率下展示了人类TRPC5与EA复合物的两种低温电镜结构，揭示了EA结合位点，并确定了受钙影响的两种主要构象。EA结合在hTRPC5的孔螺旋和S5/S6螺旋之间，形成关键的疏水和极性相互作用，强调了其特异性。TRPC5胞内结构域的钙结合诱导结构变化，使结构域稳定在紧凑的构象中。这些发现扩大了我们对TRPC5结构药理学的理解，并为研究TRPC5通道中的钙调节提供了一个框架。
期刊介绍：
Protein Science, the flagship journal of The Protein Society, is a publication that focuses on advancing fundamental knowledge in the field of protein molecules. The journal welcomes original reports and review articles that contribute to our understanding of protein function, structure, folding, design, and evolution.
Additionally, Protein Science encourages papers that explore the applications of protein science in various areas such as therapeutics, protein-based biomaterials, bionanotechnology, synthetic biology, and bioelectronics.
The journal accepts manuscript submissions in any suitable format for review, with the requirement of converting the manuscript to journal-style format only upon acceptance for publication.
Protein Science is indexed and abstracted in numerous databases, including the Agricultural & Environmental Science Database (ProQuest), Biological Science Database (ProQuest), CAS: Chemical Abstracts Service (ACS), Embase (Elsevier), Health & Medical Collection (ProQuest), Health Research Premium Collection (ProQuest), Materials Science & Engineering Database (ProQuest), MEDLINE/PubMed (NLM), Natural Science Collection (ProQuest), and SciTech Premium Collection (ProQuest).
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