6cgc

Crystal structure of human 17beta-HSD type 1 in ternary complex with 2-MeO-CC-156 and NADP+

spinqualitylabelsall models 6cgc, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6cgc is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1Å Ligands: F0A, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DHB1_HUMAN Favors the reduction of estrogens and androgens. Also has 20-alpha-HSD activity. Uses preferentially NADH. Publication Abstract from PubMed 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) plays a pivotal role in the progression of estrogen-related diseases because of its involvement in the biosynthesis of estradiol (E2), constituting a valuable therapeutic target for endocrine treatment. In the present study, we successfully cocrystallized the enzyme with the reversible inhibitor 2-methoxy-16beta-( m-carbamoylbenzyl)-E2 (2-MeO-CC-156) as well as the enzyme with the irreversible inhibitor 3-(2-bromoethyl)-16beta-( m-carbamoylbenzyl)-17beta-hydroxy-1,3,5(10)-estratriene (PBRM). The structures of ternary complexes of 17beta-HSD1-2-MeO-CC-156-NADP(+) and 17beta-HSD1-PBRM-NADP(+) comparatively show the formation of a covalent bond between His(221) and the bromoethyl side chain of the inhibitor in the PBRM structure. A dynamic process including beneficial molecular interactions that favor the specific binding of a low-reactivity inhibitor and subsequent N-alkylation event through the participation of His(221) in the enzyme catalytic site clearly demonstrates the covalent bond formation. This finding opens the door to a new design of alkyl halide-based specific covalent inhibitors as potential therapeutic agents for different enzymes, contributing to the development of highly efficient inhibitors. Combined Biophysical Chemistry Reveals a New Covalent Inhibitor with a Low-Reactivity Alkyl Halide.,Li T, Maltais R, Poirier D, Lin SX J Phys Chem Lett. 2018 Sep 20;9(18):5275-5280. doi: 10.1021/acs.jpclett.8b02225. , Epub 2018 Aug 31. PMID:30148957 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Hydroxysteroid dehydrogenase 3D structures

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