6NJ7
11-BETA DEHYDROGENASE ISOZYME 1 IN COMPLEX WITH COLLETOIC ACID
Summary for 6NJ7
| Entry DOI | 10.2210/pdb6nj7/pdb |
| Descriptor | Corticosteroid 11-beta-dehydrogenase isozyme 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (1S,4S,5S,9S)-9-hydroxy-8-methyl-4-(propan-2-yl)spiro[4.5]dec-7-ene-1-carboxylic acid, ... (4 entities in total) |
| Functional Keywords | dehydrogenase, inhibitor, complex, glucocorticoid regulation, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 132684.13 |
| Authors | Miller, D.J.,Rivas, F. (deposition date: 2019-01-02, release date: 2019-07-24, Last modification date: 2023-10-11) |
| Primary citation | Ling, T.,Miller, D.J.,Lang, W.H.,Griffith, E.,Rodriguez-Cortes, A.,El Ayachi, I.,Palacios, G.,Min, J.,Miranda-Carboni, G.,Lee, R.E.,Rivas, F. Mechanistic Insight on the Mode of Action of Colletoic Acid. J.Med.Chem., 62:6925-6940, 2019 Cited by PubMed Abstract: The natural product colletoic acid (CA) is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which primarily converts cortisone to the active glucocorticoid (GC) cortisol. Here, CA's mode of action and its potential as a chemical tool to study intracellular GC signaling in adipogenesis are disclosed. 11β-HSD1 biochemical studies of CA indicated that its functional groups at C-1, C-4, and C-9 were important for enzymatic activity; an X-ray crystal structure of 11β-HSD1 bound to CA at 2.6 Å resolution revealed the nature of those interactions, namely, a close-fitting and favorable interactions between the constrained CA spirocycle and the catalytic triad of 11β-HSD1. Structure-activity relationship studies culminated in the development of a superior CA analogue with improved target engagement. Furthermore, we demonstrate that CA selectively inhibits preadipocyte differentiation through 11β-HSD1 inhibition, suppressing other relevant key drivers of adipogenesis (i.e., PPARγ, PGC-1α), presumably by negatively modulating the glucocorticoid signaling pathway. The combined findings provide an in-depth evaluation of the mode of action of CA and its potential as a tool compound to study adipose tissue and its implications in metabolic syndrome. PubMed: 31294974DOI: 10.1021/acs.jmedchem.9b00187 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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