3RDH

X-ray induced covalent inhibition of 14-3-3

3RDH の概要

• エントリーDOI: 10.2210/pdb3rdh/pdb
• 分子名称: 14-3-3 protein zeta/delta, 4-[(E)-{4-formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]pyridin-2-yl}diazenyl]benzoic acid, NICKEL (II) ION, ... (4 entities in total)
• 機能のキーワード: phosphoser/thr-mimetic agent, phosphoserine/threonine-recognition protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P63104
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 114053.29

構造登録者

Horton, J.R.,Upadhyay, A.K.,Fu, H.,Cheng, X. (登録日: 2011-04-01, 公開日: 2011-09-28, 最終更新日: 2024-11-20)

主引用文献

Zhao, J.,Du, Y.,Horton, J.R.,Upadhyay, A.K.,Lou, B.,Bai, Y.,Zhang, X.,Du, L.,Li, M.,Wang, B.,Zhang, L.,Barbieri, J.T.,Khuri, F.R.,Cheng, X.,Fu, H.
Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor.
Proc.Natl.Acad.Sci.USA, 108:16212-16216, 2011

PubMed Abstract: The 14-3-3 family of phosphoserine/threonine-recognition proteins engage multiple nodes in signaling networks that control diverse physiological and pathophysiological functions and have emerged as promising therapeutic targets for such diseases as cancer and neurodegenerative disorders. Thus, small molecule modulators of 14-3-3 are much needed agents for chemical biology investigations and therapeutic development. To analyze 14-3-3 function and modulate its activity, we conducted a chemical screen and identified 4-[(2Z)-2-[4-formyl-6-methyl-5-oxo-3-(phosphonatooxymethyl)pyridin-2-ylidene]hydrazinyl]benzoate as a 14-3-3 inhibitor, which we termed FOBISIN (FOurteen-three-three BInding Small molecule INhibitor) 101. FOBISIN101 effectively blocked the binding of 14-3-3 with Raf-1 and proline-rich AKT substrate, 40 kD(a) and neutralized the ability of 14-3-3 to activate exoenzyme S ADP-ribosyltransferase. To provide a mechanistic basis for 14-3-3 inhibition, the crystal structure of 14-3-3ζ in complex with FOBISIN101 was solved. Unexpectedly, the double bond linking the pyridoxal-phosphate and benzoate moieties was reduced by X-rays to create a covalent linkage of the pyridoxal-phosphate moiety to lysine 120 in the binding groove of 14-3-3, leading to persistent 14-3-3 inactivation. We suggest that FOBISIN101-like molecules could be developed as an entirely unique class of 14-3-3 inhibitors, which may serve as radiation-triggered therapeutic agents for the treatment of 14-3-3-mediated diseases, such as cancer.

PubMed: 21908710
DOI: 10.1073/pnas.1100012108

実験手法

X-RAY DIFFRACTION (2.39 Å)