3V3E

Crystal Structure of the Human Nur77 Ligand-binding Domain

Summary for 3V3E

• Entry DOI: 10.2210/pdb3v3e/pdb
• Related: 3V3Q
• Descriptor: Nuclear receptor subfamily 4 group A member 1, GLYCEROL (3 entities in total)
• Functional Keywords: orphan nuclear receptor, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P22736
• Total number of polymer chains: 2
• Total formula weight: 57766.89

Authors

Zhang, Q.,Shi, C.,Yang, K.,Chen, Y.,Zhan, Y.,Wu, Q.,Lin, T. (deposition date: 2011-12-13, release date: 2012-09-26, Last modification date: 2023-11-08)

Primary citation

Zhan, Y.,Chen, Y.,Zhang, Q.,Zhuang, J.,Tian, M.,Chen, H.,Zhang, L.,Zhang, H.,He, J.,Wang, W.,Wu, R.,Wang, Y.,Shi, C.,Yang, K.,Li, A.,Xin, Y.,Li, T.Y.,Yang, J.Y.,Zheng, Z.,Yu, C.,Lin, S.,Chang, C.,Huang, P.,Lin, T.,Wu, Q.
The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK
Nat.Chem.Biol., 8:897-904, 2012

PubMed Abstract: Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chemical compound ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.

PubMed: 22983157
DOI: 10.1038/nchembio.1069

Experimental method

X-RAY DIFFRACTION (2.06 Å)