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Computational modeling of transforming growth factor β and activin a receptor complex formation in the context of promiscuous signaling regulation
Journal of Biomolecular Structure and Dynamics ( IF 2.7 ) Pub Date : 2020-06-27 , DOI: 10.1080/07391102.2020.1785330
Stephen M Farmer 1 , Claudia D Andl 1
Affiliation  

Abstract

The Transforming growth factor-beta (TGFβ) superfamily is a group of multipotent growth factors that control proliferation, quiescence and differentiation. Aberrant signal transduction and downstream target activation contribute to tumorigenesis and targeted therapy has therefore been considered a promising avenue. Using various modeling pipelines, we analyzed the structure-function relationship between ligand and receptor molecules of the TGFβ family. We further simulated the molecular docking of Galunisertib, a small molecule inhibitor targeting TGFβ signaling in cancer, which is currently undergoing FDA-approved clinical trials. We found that proprotein dimers of Activin isoforms differ at intrachain disulfide bonds, which support prior evidence of varying pro-domain stability and isoform preference. Further, mature proteins possess flexibility around conserved cystine knots to functionally interact with receptors or regulatory molecules in similar but distinct ways to TGFβ. We show that all Activin isoforms are capable of assuming a closed- or open-dimer state, revealing structural promiscuity of their open forms for receptor binding. We propose the first structural landscape for Activin receptor complexes containing a type I receptor (ACVR1B), which shares a pre-helix extension with TGFβ type I receptor (TGFβR1). Here, we artificially demonstrate that Activin can bind TGFβR1 in a TGFβ-like manner and that TGFβ1 can form signaling complexes with ACVR1B. Interestingly, Galunisertib was found to form stable inhibitory structures within the homologous kinase domains of both TGFβR1 and ACVR1B, thus halting receptor-promiscuous signaling. Overall, these observations highlight the challenges of specific TGFβ cascade targeting in the context of cancer therapies.

Communicated by Ramaswamy H. Sarma



中文翻译:

混杂信号调控背景下转化生长因子β和激活素受体复合物形成的计算模型

摘要

转化生长因子-β (TGFβ) 超家族是一组控制增殖、静止和分化的多能生长因子。异常信号转导和下游靶点激活有助于肿瘤发生,因此靶向治疗被认为是一种有前途的途径。使用各种建模管道,我们分析了 TGFβ 家族的配体和受体分子之间的结构-功能关系。我们进一步模拟了 Galunisertib 的分子对接,这是一种针对癌症中 TGFβ 信号传导的小分子抑制剂,目前正在进行 FDA 批准的临床试验。我们发现激活素同种型的前蛋白二聚体在链内二硫键处不同,这支持了不同前域稳定性和同种型偏好的先前证据。更远,成熟蛋白质在保守的胱氨酸结周围具有灵活性,可以以与 TGFβ 相似但不同的方式与受体或调节分子进行功能性相互作用。我们表明,所有 Activin 异构体都能够呈现封闭或开放二聚体状态,揭示其开放形式与受体结合的结构混杂性。我们提出了第一个包含 I 型受体 (ACVR1B) 的激活素受体复合物的结构图,它与 TGFβ I 型受体 (TGFβR1) 共享前螺旋延伸。在这里,我们人为地证明了 Activin 可以以类似 TGFβ 的方式结合 TGFβR1,并且 TGFβ1 可以与 ACVR1B 形成信号复合物。有趣的是,发现 Galunisertib 在 TGFβR1 和 ACVR1B 的同源激酶结构域内形成稳定的抑制结构,从而阻止受体混杂信号传导。全面的,

由 Ramaswamy H. Sarma 传达

更新日期:2020-06-27
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