Department of Chemistry and Molecular Biology, University of Gothenburg, Box 465, SE-40530, Gothenburg, Sweden.
Science for Life Laboratory, Department of Medicine, Solna, Karolinska Institute, SE-17165, Solna, Sweden.
Commun Biol. 2024 Jul 16;7(1):868. doi: 10.1038/s42003-024-06558-y.
Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is an attractive target for the development of modulatory compounds in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained unexplored. We present here dynamic analyses of the apo MALT1 form along with the E549A mutation. This investigation used NMR N relaxation and NOE measurements between side-chain methyl groups. Our findings confirm that MALT1 exists as a monomer in solution, and demonstrate that the domains display semi-independent movements in relation to each other. Our dynamic study, covering multiple time scales, along with the assessment of conformational populations by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, put the side chain of residue W580 in an inward position, shedding light at potential mechanisms underlying the allosteric regulation of this enzyme.
黏膜相关淋巴组织淋巴瘤易位蛋白 1（MALT1）是一种有吸引力的治疗淋巴瘤和其他癌症的调节化合物开发靶点。尽管已经通过 X 射线分析确定了 MALT1 的三维结构，但它在溶液中的动态行为仍未被探索。我们在这里介绍了 apo MALT1 形式以及 E549A 突变的动态分析。这项研究使用了 NMR N 弛豫和侧链甲基之间的 NOE 测量。我们的发现证实 MALT1 在溶液中以单体形式存在，并表明各结构域彼此之间呈现半独立的运动。我们的动力学研究涵盖了多个时间尺度，并通过分子动力学模拟、Alpha Fold 建模和 PCA 分析评估了构象种群，将残基 W580 的侧链置于向内位置，为该酶的变构调节的潜在机制提供了线索。
