Gaczynska Maria, Osmulski Pawel A
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio , San Antonio, Texas.
Antioxid Redox Signal. 2014 Dec 10;21(17):2286-301. doi: 10.1089/ars.2013.5816. Epub 2014 Feb 21.
The proteasome is the essential protease that is responsible for regulated cleavage of the bulk of intracellular proteins. Its central role in cellular physiology has been exploited in therapies against aggressive cancers where proteasome-specific competitive inhibitors that block proteasome active centers are very effectively used. However, drugs regulating this essential protease are likely to have broader clinical usefulness. The non-catalytic sites of the proteasome emerge as an attractive alternative target in search of highly specific and diverse proteasome regulators.
Crystallographic models of the proteasome leave the false impression of fixed structures with minimal molecular dynamics lacking long-distance allosteric signaling. However, accumulating biochemical and structural observations strongly support the notion that the proteasome is regulated by precise allosteric interactions arising from protein dynamics, encouraging the active search for allosteric regulators. Here, we discuss properties of several promising compounds that affect substrate gating and processing in antechambers, and interactions of the catalytic core with regulatory proteins.
Given the structural complexity of proteasome assemblies, it is a painstaking process to better understand their allosteric regulation and molecular dynamics. Here, we discuss the challenges and achievements in this field. We place special emphasis on the role of atomic force microscopy imaging in probing the allostery and dynamics of the proteasome, and in dissecting the mechanisms involving small-molecule allosteric regulators.
New small-molecule allosteric regulators may become a next generation of drugs targeting the proteasome, which is critical to the development of new therapies in cancers and other diseases.
蛋白酶体是负责大量细胞内蛋白质有序切割的关键蛋白酶。其在细胞生理学中的核心作用已被应用于侵袭性癌症的治疗，其中阻断蛋白酶体活性中心的蛋白酶体特异性竞争性抑制剂被非常有效地使用。然而，调节这种关键蛋白酶的药物可能具有更广泛的临床用途。蛋白酶体的非催化位点成为寻找高度特异性和多样化蛋白酶体调节剂的有吸引力的替代靶点。
蛋白酶体的晶体学模型给人留下了固定结构的错误印象，其分子动力学极小，缺乏长距离变构信号。然而，越来越多的生化和结构观察结果有力地支持了蛋白酶体受蛋白质动力学产生的精确变构相互作用调节的观点，这鼓励了对变构调节剂的积极寻找。在此，我们讨论了几种有前景的化合物的特性，这些化合物影响前室中的底物门控和加工，以及催化核心与调节蛋白的相互作用。
鉴于蛋白酶体组装体的结构复杂性，更好地理解其变构调节和分子动力学是一个艰苦的过程。在此，我们讨论了该领域的挑战和成就。我们特别强调原子力显微镜成像在探测蛋白酶体的变构和动力学以及剖析涉及小分子变构调节剂的机制方面的作用。
新的小分子变构调节剂可能成为靶向蛋白酶体的下一代药物，这对癌症和其他疾病新疗法的开发至关重要。
