Hypoxia-selective allosteric destabilization of activin receptor-like kinases: A potential therapeutic avenue for prophylaxis of heterotopic ossification.
Hypoxia-selective allosteric destabilization of activin receptor-like kinases: A potential therapeutic avenue for prophylaxis of heterotopic ossification.
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DOI：
10.1016/j.bone.2018.03.027
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发表时间：
2018-07
期刊：
影响因子：
4.1
通讯作者：
Groppe, Jay C.
中科院分区：
文献类型：
--
作者：
Lu, Guorong;Tandang-Silvas, Mary R.;Dawson, Alyssa C.;Dawson, Trenton J.;Groppe, Jay C.
关键词：
异位骨化（HO）是一种病理性骨外骨骼形成，可由爆炸伤、严重烧伤、骨科手术和骨形态发生蛋白（BMP）信号传导通路组分ACVR 1/ALK 2受体丝氨酸-苏氨酸（蛋白）激酶的功能获得性突变引起，可导致进行性骨化性纤维发育不良（FOP）。在骨形态发生中发挥作用的所有三种ALK（-2、-3、-6）都有助于创伤诱导的HO，因此是经过充分验证的药理学靶点。也就是说，由于500多种人类蛋白激酶的活性位点的保守性质，抑制剂（通常为ATP结合的竞争剂）的开发固有地困难。由于这些酶通过固有的可塑性调节，药理学伴侣样药物结合到另一个（变构）网站可以假设调节激酶的构象和活性。为了测试这种机制，通过虚拟库中药物样化合物的超级计算机对接，靶向主要由关键变构子结构形成的ALK 2激酶的表面口袋。随后，在体外用纯化的重组激酶蛋白进一步筛选对接命中的效果。一个家庭的化合物与终端氢键受体基团被确定为显着不稳定的蛋白质，废除活动。去稳定是pH依赖性的，puerectin介导的电离的变构子结构内的组氨酸与pH值降低。在体内，非天然蛋白质降解的蛋白酶体复合物中的蛋白水解，或细胞垃圾桶，允许出现的治疗剂，抑制通过降解过度活跃的蛋白质参与的疾病和病症的病理。由于HO是由软组织创伤和随后的缺氧触发的，ALK不稳定对缺氧pH的依赖性赋予了变构抑制剂的选择性疗效，为安全的预防性使用提供了可能性。
Heterotopic ossification (HO), the pathological extraskeletal formation of bone, can arise from blast injuries, severe burns, orthopedic procedures and gain-of-function mutations in a component of the bone morphogenetic protein (BMP) signaling pathway, the ACVR1/ALK2 receptor serine-threonine (protein) kinase, causative of Fibrodysplasia Ossificans Progressiva (FOP). All three ALKs (−2, −3, −6) that play roles in bone morphogenesis contribute to trauma-induced HO, hence are well-validated pharmacological targets. That said, development of inhibitors, typically competitors of ATP binding, is inherently difficult due to the conserved nature of the active site of the 500+ human protein kinases. Since these enzymes are regulated via inherent plasticity, pharmacological chaperone-like drugs binding to another (allosteric) site could hypothetically modulate kinase conformation and activity. To test for such a mechanism, a surface pocket of ALK2 kinase formed largely by a key allosteric substructure was targeted by supercomputer docking of drug-like compounds from a virtual library. Subsequently, the effects of docked hits were further screened in vitro with purified recombinant kinase protein. A family of compounds with terminal hydrogen-bonding acceptor groups was identified that significantly destabilized the protein, abolishing activity. Destabilization was pH-dependent, putatively mediated by ionization of a histidine within the allosteric substructure with decreasing pH. In vivo, nonnative proteins are degraded by proteolysis in the proteasome complex, or cellular trashcan, allowing for the emergence of therapeutics that inhibit through degradation of over-active proteins implicated in the pathology of diseases and disorders. Because HO is triggered by soft-tissue trauma and ensuing hypoxia, dependency of ALK destabilization on hypoxic pH imparts selective efficacy on the allosteric inhibitors, providing potential for safe prophylactic use.
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DOI：
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发表时间：
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期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
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作者：
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