6CGE

Crystal structure of human 17beta-HSD type 1 in ternary complex with PBRM and NADP+

Summary for 6CGE

• Entry DOI: 10.2210/pdb6cge/pdb
• Descriptor: Estradiol 17-beta-dehydrogenase 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-{[(14beta,16alpha,17alpha)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methyl}benzamide, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, hydroxysteroid dehydrogenase, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 72457.77

Authors

Li, T.,Lin, S.X. (deposition date: 2018-02-20, release date: 2019-01-16, Last modification date: 2024-10-23)

Primary citation

Li, T.,Maltais, R.,Poirier, D.,Lin, S.X.
Combined Biophysical Chemistry Reveals a New Covalent Inhibitor with a Low-Reactivity Alkyl Halide.
J Phys Chem Lett, 9:5275-5280, 2018

PubMed Abstract: 17β-Hydroxysteroid dehydrogenase type 1 (17β-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-16β-( m-carbamoylbenzyl)-E2 (2-MeO-CC-156) as well as the enzyme with the irreversible inhibitor 3-(2-bromoethyl)-16β-( m-carbamoylbenzyl)-17β-hydroxy-1,3,5(10)-estratriene (PBRM). The structures of ternary complexes of 17β-HSD1-2-MeO-CC-156-NADP and 17β-HSD1-PBRM-NADP comparatively show the formation of a covalent bond between His 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 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.

PubMed: 30148957
DOI: 10.1021/acs.jpclett.8b02225

Experimental method

X-RAY DIFFRACTION (2.2 Å)