8RVF
CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE IN COMPLEX WITH COMPOUND 5
This is a non-PDB format compatible entry.
Summary for 8RVF
| Entry DOI | 10.2210/pdb8rvf/pdb |
| Descriptor | Monoglyceride lipase, [6-[[2,2-bis(fluoranyl)-1$l^{4},3-diaza-2$l^{4}-boratricyclo[7.3.0.0^{3,7}]dodeca-1(12),4,6,8,10-pentaen-8-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]-[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]methanone, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | alpha/beta hydrolase, hydrolase, serine esterase; |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 36183.12 |
| Authors | Leibrock, L.,Hentsch, A.,Nazare, M.,Grether, U.,Kuhn, B.,Blaising, J.,Benz, J. (deposition date: 2024-02-01, release date: 2025-02-12, Last modification date: 2025-04-09) |
| Primary citation | Hentsch, A.,Guberman, M.,Radetzki, S.,Kaushik, S.,Huizenga, M.,He, Y.,Contzen, J.,Kuhn, B.,Benz, J.,Schippers, M.,Paul, J.,Leibrock, L.,Collin, L.,Wittwer, M.,Topp, A.,O'Hara, F.,Heer, D.,Hochstrasser, R.,Blaising, J.,von Kries, J.P.,Mu, L.,van der Stelt, M.,Mergenthaler, P.,Lipstein, N.,Grether, U.,Nazare, M. Highly Specific Miniaturized Fluorescent Monoacylglycerol Lipase Probes Enable Translational Research. J.Am.Chem.Soc., 147:10188-10202, 2025 Cited by PubMed Abstract: Monoacylglycerol lipase (MAGL) is the pivotal catabolic enzyme responsible for signal termination in the endocannabinoid system. Inhibition of MAGL offers unique advantages over the direct activation of cannabinoid receptors in treating cancer, metabolic disorders, and inflammatory diseases. Although specific fluorescent molecular imaging probes are commonly used for the real-time analysis of the localization and distribution of drug targets in cells, they are almost invariably composed of a linker connecting the pharmacophore with a large fluorophore. In this study, we have developed miniaturized fluorescent probes targeting MAGL by incorporating a highly fluorescent boron-dipyrromethene (BODIPY) moiety into the inhibitor structure that interacts with the MAGL active site. These miniaturized fluorescent probes exhibit favorable drug-like properties such as high solubility and permeability, picomolar potency for MAGL across various species, and high cell selectivity and specificity. A range of translational investigations were conducted, including cell-free fluorescence polarization assays, fluorescence-activated cell sorting analysis, and confocal fluorescence microscopy of live cancer cells, live primary neurons, and human-induced pluripotent stem cell-derived brain organoids. Furthermore, the application of red-shifted analogs or F positron emission labeling illustrated the significant versatility and adaptability of the fluorescent ligands in various experimental contexts. PubMed: 40063733DOI: 10.1021/jacs.4c15223 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.43 Å) |
Structure validation
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