6wkz
From Proteopedia
Cocomplex structure of Deoxyhypusine synthase with inhibitor 6-[(1R)-2-AMINO-1-PHENYLETHYL]-3-(PYRIDIN-3-YL)-4H,5H,6H,7H-THIENO[2,3-C]PYRIDIN-7-ONE
Structural highlights
FunctionDHYS_HUMAN Catalyzes the NAD-dependent oxidative cleavage of spermidine and the subsequent transfer of the butylamine moiety of spermidine to the epsilon-amino group of a specific lysine residue of the eIF-5A precursor protein to form the intermediate deoxyhypusine residue. Publication Abstract from PubMedDeoxyhypusine synthase (DHPS) is the primary enzyme responsible for the hypusine modification and, thereby, activation of the eukaryotic translation initiation factor 5A (eIF5A), which is key in regulating the protein translation processes associated with tumor proliferation. Although DHPS inhibitors could be a promising therapeutic option for treating cancer, only a few studies reported druglike compounds with this inhibition property. Thus, in this work, we designed and synthesized a new chemical series possessing fused ring scaffolds designed from high-throughput screening hit compounds, discovering a 5,6-dihydrothieno[2,3-c]pyridine derivative (26d) with potent inhibitory activity; furthermore, the X-ray crystallographic analysis of the DHPS complex with 26d demonstrated a distinct allosteric binding mode compared to a previously reported inhibitor. These findings could be significantly useful in the functional analysis of conformational changes in DHPS as well as the structure-based design of allosteric inhibitors. New Series of Potent Allosteric Inhibitors of Deoxyhypusine Synthase.,Tanaka Y, Kurasawa O, Yokota A, Klein MG, Saito B, Matsumoto S, Okaniwa M, Ambrus-Aikelin G, Uchiyama N, Morishita D, Kimura H, Imamura S ACS Med Chem Lett. 2020 Jul 30;11(8):1645-1652. doi:, 10.1021/acsmedchemlett.0c00331. eCollection 2020 Aug 13. PMID:34345355[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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