Structural basis for the stabilization of amyloidogenic immunoglobulin light chains by hydantoins |
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| Institution: | 1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA;2. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA;3. Departments of Molecular Genetics, Biochemistry and Chemistry, The University of Toronto, Toronto, ON M5S1A8, Canada;4. Automated Synthesis Facility, The Scripps Research Institute, La Jolla, CA 92037, USA;5. The Hospital for Sick Children, Program in Molecular Medicine, 555 University Avenue, Toronto, ON M5G1X8, Canada;6. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA;7. Section of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA;8. The Amyloidosis Center, Boston University School of Medicine, Boston, MA 02118, USA;1. School of Engineering and Applied Sciences, United States;2. Francis Bitter Magnet Lab, Department of Chemistry, MIT, United States;3. Department of Chemistry, Aarhus University, Denmark;4. School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, United States;1. Department of Biophysics, Kobe University Graduate School of Health Science, 7-10-2, Tomogaoka, Suma-ku, Kobe 654-0142, Japan;2. Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University, Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan;3. Department of Medicine, Hyogo Prefectural Kakogawa Hospital, 770-1 Awazu, Kakogawa 675-8555, Japan;4. College of Nursing Art and Science, University of Hyogo, 13-71, Kita-Oji-cho, Akashi 673-8588, Japan;5. Department of Nutrition and Food Science, Kobe Women’s University, Graduate School of Life Sciences, 2-1, Higashisuma Aoyama, Suma-ku, Kobe 654-8585, Japan;1. Microbiology and Molecular Biology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh, India;1. Department of Organic Chemistry, Indian Institute of Science, Bangalore, Karnataka 560012, India;2. Department of Biochemistry, Washington University, MO, USA |
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| Abstract: | Misfolding and aggregation of immunoglobulin light chains (LCs) leads to the degeneration of post-mitotic tissue in the disease immunoglobulin LC amyloidosis (AL). We previously reported the discovery of small molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which slow or stop the LC aggregation cascade at the outset. A predominant structural category of kinetic stabilizers emerging from the high-throughput screen are coumarins substituted at the 7-position, which bind at the interface between the two variable domains of the light chain dimer. Here, we report the binding mode of another, more polar, LC kinetic stabilizer chemotype, 3,5-substituted hydantoins. Computational docking, solution nuclear magnetic resonance experiments, and x-ray crystallography show that the aromatic substructure emerging from the hydantoin 3-position occupies the same LC binding site as the coumarin ring. Notably, the hydantoin ring extends beyond the binding site mapped out by the coumarin hits. The hydantoin ring makes hydrogen bonds with both LC monomers simultaneously. The alkyl substructure at the hydantoin 5-position partially occupies a novel binding pocket proximal to the pocket occupied by the coumarin substructure. Overall, the hydantoin structural data suggest that a larger area of the LC variable-domain–variable-domain dimer interface is amenable to small molecule binding than previously demonstrated, which should facilitate development of more potent full-length LC kinetic stabilizers. |
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