Download MendeleyStructure of human spermine oxidase in complex with a highly selective allosteric inhibitor.
Diaz, E., Adhikary, S., Tepper, A.W.J.W., Riley, D., Ortiz-Meoz, R., Krosky, D., Buyck, C., Lamenca, C.M., Llaveria, J., Fang, L., Kalin, J.H., Klaren, V.N.A., Fahmy, S., Shaffer, P.L., Kirkpatrick, R., Carbajo, R.J., Thomsen, M., Impagliazzo, A.(2022) Commun Biol 5: 787-787
- PubMed: 35931745
- DOI: https://doi.org/10.1038/s42003-022-03735-9
- Primary Citation of Related Structures:
7OXL, 7OY0 - PubMed Abstract:
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?? 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?? 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.
Organizational Affiliation:
Janssen Research & Development, Welsh & McKean Roads, Spring House, PA, 19477-0776, USA.
