Department of Sciences, School of Interdisciplinary Engineering and Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
J Biomol Struct Dyn. 2024 Feb-Mar;42(4):2170-2196. doi: 10.1080/07391102.2023.2201332. Epub 2023 Apr 17.
Calcium signaling has been identified as an important phenomenon in a plethora of cellular processes. Inositol 1,4,5-trisphosphate receptors (IPRs) are ER-residing intracellular calcium (Ca) release channels responsible for cell bioenergetics by transferring calcium from the ER to the mitochondria. The recent availability of full-length IPR channel structure has enabled the researchers to design the IP competitive ligands and reveal the channel gating mechanism by elucidating the conformational changes induced by ligands. However, limited knowledge is available for IPR antagonists and the exact mechanism of action of these antagonists within a tumorigenic environment of a cell. Here in this review a summarized information about the role of IPR in cell proliferation and apoptosis has been discussed. Moreover, structure and gating mechanism of IPR in the presence of antagonists have been provided in this review. Additionally, compelling information about ligand-based studies (both agonists and antagonists) has been discussed. The shortcomings of these studies and the challenges toward the design of potent IPR modulators have also been provided in this review. However, the conformational changes induced by antagonists for channel gating mechanism still display some major drawbacks that need to be addressed. However, the design, synthesis and availability of isoform-specific antagonists is a rather challenging one due to intra-structural similarity within the binding domain of each isoform. HighlightsThe intricate complexity of IPR's in cellular processes declares them an important target whereby, the recently solved structure depicts the receptor's potential involvement in a complex network of processes spanning from cell proliferation to cell death.Pharmacological inhibition of IPR attenuates the proliferation or invasiveness of cancers, thus inducing necrotic cell death.Despite significant advancements, there is a tremendous need to design new potential hits to target IPR, based upon 3D structural features and pharmacophoric patterns.Communicated by Ramaswamy H. Sarma.
钙信号已被确定为众多细胞过程中的重要现象。肌醇 1,4,5-三磷酸受体 (IPR) 是内质网驻留的细胞内钙 (Ca) 释放通道，通过将 Ca 从内质网转移到线粒体来负责细胞生物能量。全长 IPR 通道结构的最新可用性使研究人员能够设计 IP 竞争配体，并通过阐明配体诱导的构象变化来揭示通道门控机制。然而，对于 IPR 拮抗剂的了解有限，并且这些拮抗剂在细胞的致瘤环境中的作用机制尚不清楚。在本文综述中，讨论了 IPR 在细胞增殖和细胞凋亡中的作用的综合信息。此外，本文还提供了存在拮抗剂时 IPR 的结构和门控机制。此外，还讨论了基于配体的研究（激动剂和拮抗剂）的相关信息。本文还提供了这些研究的局限性以及针对有效 IPR 调节剂设计的挑战。然而，拮抗剂诱导的通道门控机制的构象变化仍然存在一些需要解决的主要缺点。然而，由于每个同工型结合域内的结构相似性，同工型特异性拮抗剂的设计、合成和可用性仍然是一个相当具有挑战性的问题。重点IPR 在细胞过程中的复杂复杂性表明它们是一个重要的靶点，最近解决的结构表明该受体可能参与了从细胞增殖到细胞死亡的复杂过程网络。IPR 的药理学抑制可减弱癌症的增殖或侵袭性，从而诱导坏死性细胞死亡。尽管取得了重大进展，但仍需要根据 3D 结构特征和药效团模式设计新的潜在靶点来靶向 IPR。
