Department of Chemistry, University of the Pacific, Stockton, California 95211, United States.
Department of Chemistry and Biochemistry, University of California, Merced, California 95340, United States.
J Med Chem. 2024 May 9;67(9):7359-7372. doi: 10.1021/acs.jmedchem.4c00177. Epub 2024 Apr 26.
Systematic analysis of molecular recognition is critical for understanding the biological function of macromolecules. For the immunomodulatory protein D-dopachrome tautomerase (D-DT), the mechanism of protein-ligand interactions is poorly understood. Here, 17 carefully designed protein variants and wild type (WT) D-DT were interrogated with an array of complementary techniques to elucidate the structural basis of ligand recognition. Utilization of a substrate and two selective inhibitors with distinct binding profiles offered previously unseen mechanistic insights into D-DT-ligand interactions. Our results demonstrate that the C-terminal region serves a key role in molecular recognition via regulation of the active site opening, protein-ligand interactions, and conformational flexibility of the pocket's environment. While our study is the first comprehensive analysis of molecular recognition for D-DT, the findings reported herein promote the understanding of protein functionality and enable the design of new structure-based drug discovery projects.
系统分析分子识别对于理解生物大分子的功能至关重要。对于免疫调节蛋白 D-多巴色素互变异构酶（D-DT），其蛋白-配体相互作用的机制尚未完全了解。在这里，通过一系列互补技术研究了 17 种精心设计的蛋白质变体和野生型（WT）D-DT，以阐明配体识别的结构基础。利用具有不同结合特征的底物和两种选择性抑制剂，为 D-DT-配体相互作用提供了前所未有的机制见解。我们的结果表明，C 末端区域通过调节活性位点开口、蛋白-配体相互作用以及口袋环境的构象灵活性，在分子识别中发挥关键作用。虽然我们的研究是对 D-DT 的分子识别进行的首次全面分析，但本文报道的研究结果促进了对蛋白功能的理解，并为新的基于结构的药物发现项目的设计提供了依据。
