4WHF

Crystal Structure of TR3 LBD in complex with 1-(3,4,5-trihydroxyphenyl)decan-1-one

Summary for 4WHF

• Entry DOI: 10.2210/pdb4whf/pdb
• Related: 4re8 4ree 4ref 4whg
• Descriptor: Nuclear receptor subfamily 4 group A member 1, GLYCEROL, 1-(3,4,5-trihydroxyphenyl)decan-1-one, ... (4 entities in total)
• Functional Keywords: lbd, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P22736
• Total number of polymer chains: 2
• Total formula weight: 58231.44

Authors

Li, F.W.,Cai, Q.X.,Li, A.Z.,Tian, X.Y.,Wang, W.J.,Wang, Y.,Hou, P.P.,Wu, Q.,Lin, T.W. (deposition date: 2014-09-22, release date: 2015-09-09, Last modification date: 2024-03-20)

Primary citation

Wang, W.J.,Wang, Y.,Hou, P.P.,Li, F.W.,Zhou, B.,Chen, H.Z.,Bian, X.L.,Cai, Q.X.,Xing, Y.Z.,He, J.P.,Zhang, H.,Huang, P.Q.,Lin, T.,Wu, Q.
Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity
Chem.Biol., 22:1040-1051, 2015

PubMed Abstract: Apoptotic resistance is becoming a significant obstacle for cancer therapy as the majority of treatment takes the route of apoptotic induction. It is of great importance to develop an alternative strategy to induce cancer cell death. We previously reported that autophagic cell death mediated by nuclear receptor TR3 and driven by a chemical agonist, 1-(3,4,5-trihydroxyphenyl)nonan-1-one (THPN), is highly effective in the therapy of melanoma but not any other cancer types. Here, we discovered that the insensitivity of cancer cells to THPN originated from a high cellular Akt2 activity. Akt2 phosphorylation interferes with TR3 export to cytoplasm and targeting to mitochondria, which lead to the autophagic induction. Therefore, the TR3-mediated autophagy could be effectively induced in the otherwise insensitive cells by downregulating Akt2 activity. Highly effective antineoplastic compounds are developed through optimizing the structure of THPN. This study implicates a general strategy for cancer therapy by the induction of autophagic cell death.

PubMed: 26235054
DOI: 10.1016/j.chembiol.2015.06.023

Experimental method

X-RAY DIFFRACTION (2.27 Å)