9rax
The L1 amyloid-beta(1-40)fibril in the presence of anle138b (pre-treatment)
Structural highlights
FunctionB4DM00_HUMAN Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.[RuleBase:RU367156] Publication Abstract from PubMedAlzheimer's disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Abeta) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug candidate small molecule anle138b and lipidic Abeta(4)(0) fibrils of type 1 (L1). L1 fibrils were previously shown to closely resemble fibrils from Alzheimer's patients. Using high-resolution structural biology techniques, including cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy enhanced by dynamic nuclear polarization (DNP), and molecular dynamics (MD) simulations, we find that anle138b selectively binds to a cavity within the fibril. This structural insight provides a deeper understanding of a potential drug-binding mechanism at the atomic level and may inform the development of therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. This may suggest a mechanistic connection to its previously reported activity in animal models of Alzheimer's disease. Anle138b binds predominantly to the central cavity in lipidic Abeta(4)(0) fibrils and modulates fibril formation.,Han M, Frieg B, Matthes D, Leonov A, Ryazanov S, Giller K, Nimerovsky E, Stampolaki M, Xue K, Overkamp K, Dienemann C, Riedel D, Giese A, Becker S, de Groot BL, Schroder GF, Andreas LB, Griesinger C Nat Commun. 2025 Oct 3;16(1):8850. doi: 10.1038/s41467-025-64443-6. PMID:41044155[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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