6WL6

Cocomplex structure of Deoxyhypusine synthase with inhibitor 6-[(2R)-1-AMINO-4-METHYLPENTAN-2-YL]-3-(PYRIDIN-3-YL)-4H,5H,6H,7H-THIENO[2,3-C]PYRIDIN-7-ONE

Summary for 6WL6

• Entry DOI: 10.2210/pdb6wl6/pdb
• Related: 5V15 5V2E 5V4J
• Descriptor: Deoxyhypusine synthase, 6-[(2R)-1-amino-4-methylpentan-2-yl]-3-(pyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (3 entities in total)
• Functional Keywords: deoxyhypusine, inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 83086.15

Authors

Klein, M.G.,Ambrus-Aikelin, G. (deposition date: 2020-04-18, release date: 2020-08-19, Last modification date: 2023-10-18)

Primary citation

Tanaka, Y.,Kurasawa, O.,Yokota, A.,Klein, M.G.,Saito, B.,Matsumoto, S.,Okaniwa, M.,Ambrus-Aikelin, G.,Uchiyama, N.,Morishita, D.,Kimura, H.,Imamura, S.
New Series of Potent Allosteric Inhibitors of Deoxyhypusine Synthase.
Acs Med.Chem.Lett., 11:1645-1652, 2020

PubMed Abstract: Deoxyhypusine 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-]pyridine derivative () with potent inhibitory activity; furthermore, the X-ray crystallographic analysis of the DHPS complex with 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.

PubMed: 34345355
DOI: 10.1021/acsmedchemlett.0c00331

Experimental method

X-RAY DIFFRACTION (2.12 Å)