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Structure of human spermine oxidase in complex with a highly selective allosteric inhibitor

Human spermine oxidase (hSMOX) plays a central role in polyamine catabolism. Due to its association with several pathological processes, including inflammation and cancer, hSMOX has garnered interest as a possible therapeutic target. Therefore, determination of the structure of hSMOX is an important...

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Detalles Bibliográficos
Autores principales: Diaz, Elsie, Adhikary, Suraj, Tepper, Armand W. J. W., Riley, Daniel, Ortiz-Meoz, Rodrigo, Krosky, Daniel, Buyck, Christophe, Lamenca, Carolina Martinez, Llaveria, Josep, Fang, Lichao, Kalin, Jay H., Klaren, Vincent N. A., Fahmy, Shorouk, Shaffer, Paul L., Kirkpatrick, Robert, Carbajo, Rodrigo J., Thomsen, Maren, Impagliazzo, Antonietta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355956/
https://www.ncbi.nlm.nih.gov/pubmed/35931745
http://dx.doi.org/10.1038/s42003-022-03735-9
Descripción
Sumario:Human spermine oxidase (hSMOX) plays a central role in polyamine catabolism. Due to its association with several pathological processes, including inflammation and cancer, hSMOX has garnered interest as a possible therapeutic target. Therefore, determination of the structure of hSMOX is an important step to enable drug discovery and validate hSMOX as a drug target. Using insights from hydrogen/deuterium exchange mass spectrometry (HDX-MS), we engineered a hSMOX construct to obtain the first crystal structure of hSMOX bound to the known polyamine oxidase inhibitor MDL72527 at 2.4 Å resolution. While the overall fold of hSMOX is similar to its homolog, murine N1-acetylpolyamine oxidase (mPAOX), the two structures contain significant differences, notably in their substrate-binding domains and active site pockets. Subsequently, we employed a sensitive biochemical assay to conduct a high-throughput screen that identified a potent and selective hSMOX inhibitor, JNJ-1289. The co-crystal structure of hSMOX with JNJ-1289 was determined at 2.1 Å resolution, revealing that JNJ-1289 binds to an allosteric site, providing JNJ-1289 with a high degree of selectivity towards hSMOX. These results provide crucial insights into understanding the substrate specificity and enzymatic mechanism of hSMOX, and for the design of highly selective inhibitors.