7OXL

Crystal structure of human Spermine Oxidase

Summary for 7OXL

• Entry DOI: 10.2210/pdb7oxl/pdb
• Descriptor: Spermine oxidase,Spermine oxidase,Spermine oxidase, FAD-MDL72527 adduct, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: spermine oxidase, polyamine metabolism, spermine, spermidine, unknown function
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 56018.63

Authors

Impagliazzo, A.,Johannsson, S.,Thomsen, M.,Krapp, S. (deposition date: 2021-06-22, release date: 2022-07-13, Last modification date: 2024-11-13)

Primary citation

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.
Structure of human spermine oxidase in complex with a highly selective allosteric inhibitor.
Commun Biol, 5:787-787, 2022

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 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.

PubMed: 35931745
DOI: 10.1038/s42003-022-03735-9

Experimental method

X-RAY DIFFRACTION (2.4 Å)