7Y62

Crystal structure of human TFEB HLHLZ domain

Summary for 7Y62

• Entry DOI: 10.2210/pdb7y62/pdb
• Descriptor: Transcription factor EB (2 entities in total)
• Functional Keywords: transcription factor, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 17932.83

Authors

Yang, G.,Li, P.,Lin, Y.,Liu, Z.,Sun, H.,Zhao, Z.,Fang, P.,Wang, J. (deposition date: 2022-06-18, release date: 2023-03-22, Last modification date: 2023-11-29)

Primary citation

Lin, Y.,Shi, Q.,Yang, G.,Shi, F.,Zhou, Y.,Wang, T.,Xu, P.,Li, P.,Liu, Z.,Sun, H.,Zhao, Z.,Ding, K.,Wang, Z.,Feng, H.,Yu, B.,Fang, P.,Wang, J.
A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB.
Proc.Natl.Acad.Sci.USA, 120:e2213670120-e2213670120, 2023

PubMed Abstract: Autophagy supports the fast growth of established tumors and promotes tumor resistance to multiple treatments. Inhibition of autophagy is a promising strategy for tumor therapy. However, effective autophagy inhibitors suitable for clinical use are currently lacking. There is a high demand for identifying novel autophagy drug targets and potent inhibitors with drug-like properties. The transcription factor EB (TFEB) is the central transcriptional regulator of autophagy, which promotes lysosomal biogenesis and functions and systematically up-regulates autophagy. Despite extensive evidence that TFEB is a promising target for autophagy inhibition, no small molecular TFEB inhibitors were reported. Here, we show that an United States Food and Drug Administration (FDA)-approved drug Eltrombopag (EO) binds to the basic helix-loop-helix-leucine zipper domain of TFEB, specifically the bottom surface of helix-loop-helix to clash with DNA recognition, and disrupts TFEB-DNA interaction in vitro and in cellular context. EO selectively inhibits TFEB's transcriptional activity at the genomic scale according to RNA sequencing analyses, blocks autophagy in a dose-dependent manner, and increases the sensitivity of glioblastoma to temozolomide in vivo. Together, this work reveals that TFEB is targetable and presents the first direct TFEB inhibitor EO, a drug compound with great potential to benefit a wide range of cancer therapies by inhibiting autophagy.

PubMed: 36749723
DOI: 10.1073/pnas.2213670120

Experimental method

X-RAY DIFFRACTION (2 Å)