9SWH

Crystal structure of aldo-keto reductase 1C3 (AKR1C3) in complex with NADP+ and Myxoglucamide A

This is a non-PDB format compatible entry.

Summary for 9SWH

• Entry DOI: 10.2210/pdb9swh/pdb
• Descriptor: Aldo-keto reductase family 1 member C3, Myxoglucamide A, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: steroid reductase, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 81598.19

Authors

Siemon, T.,Broenstrup, M.,Blankenfeldt, W. (deposition date: 2025-10-06, release date: 2026-08-26)

Primary citation

Siemon, T.,Mishra, V.K.,Zhao, M.,Bussow, K.,Popoff, A.,Fu, C.,Muller, R.,Jansch, L.,Blankenfeldt, W.,Bronstrup, M.
Synthesis and Activity-Based Protein Profiling Identifies Aldo-Keto Reductase 1C3 as Target Protein of Myxoglucamides.
Angew.Chem.Int.Ed.Engl., :e6489568-e6489568, 2026

PubMed Abstract: Myxoglucamides, natural products recently isolated from Cystobacterineae sp., are featured by an unprecedented vinyl-substituted α-keto-γ-amino acid that is linked to a glycosylated 14-methyl-pentadecanoic acid. Thus, they unite elements from three biomolecular classes in a compact glycolipopeptide. To elucidate the biological relevance of this arrangement, we searched for molecular targets by activity-based protein profiling (ABPP)-although a phenotypic bioactivity has not been reported. An access to the compound class was established through the first total synthesis of myxoglucamide A in 11 steps. A proteome-wide ABPP study led to the identification of aldo-keto reductase 1C3 (AKR1C3) as the primary target of myxoglucamides in human cells. AKR1C3 is an oncogenic factor involved in prostaglandin and steroid synthesis, promoting the growth, proliferation, and metastasis of carcinoma cells. The functional inhibition of AKR1C3 by a competitive mechanism (IC = 1.61 µm) was validated in vitro, and 20 analogs provided structure-activity relationships and more potent analogs (IC = 181 nm). Biophysical interactions were quantified by thermal shift assays, and essential molecular protein-ligand interactions were characterized by X-ray crystallography at 2.0 Å resolution. The study implies that the search for targets of natural products is rewarding even in the absence of an initial phenotypic activity.

PubMed: 42573019
DOI: 10.1002/anie.6489568

Experimental method

X-RAY DIFFRACTION (1.99 Å)