View source for 7y62


==Crystal structure of human TFEB HLHLZ domain==
<StructureSection load='7y62' size='340' side='right'caption='[[7y62]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7y62]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Y62 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Y62 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7y62 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7y62 OCA], [https://pdbe.org/7y62 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7y62 RCSB], [https://www.ebi.ac.uk/pdbsum/7y62 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7y62 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/TFEB_HUMAN TFEB_HUMAN] MiT family translocation renal cell carcinoma. 
== Function ==
[https://www.uniprot.org/uniprot/TFEB_HUMAN TFEB_HUMAN] Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:30120233, PubMed:31672913, PubMed:35662396). Specifically recognizes and binds E-box sequences (5'-CANNTG-3'); efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFE3 or MITF (PubMed:1748288, PubMed:19556463, PubMed:29146937). Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, TFEB phosphorylation by MTOR promotes its cytosolic retention and subsequent inactivation (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:35662396). Upon starvation or lysosomal stress, inhibition of MTOR induces TFEB dephosphorylation, resulting in nuclear localization and transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:35662396). Specifically recognizes and binds the CLEAR-box sequence (5'-GTCACGTGAC-3') present in the regulatory region of many lysosomal genes, leading to activate their expression, thereby playing a central role in expression of lysosomal genes (PubMed:19556463, PubMed:22692423). Regulates lysosomal positioning in response to nutrient deprivation by promoting the expression of PIP4P1 (PubMed:29146937). Acts as a positive regulator of autophagy by promoting expression of genes involved in autophagy (PubMed:21617040, PubMed:22576015, PubMed:23434374, PubMed:27278822). In association with TFE3, activates the expression of CD40L in T-cells, thereby playing a role in T-cell-dependent antibody responses in activated CD4(+) T-cells and thymus-dependent humoral immunity (By similarity). Specifically recognizes the gamma-E3 box, a subset of E-boxes, present in the heavy-chain immunoglobulin enhancer (PubMed:2115126). Plays a role in the signal transduction processes required for normal vascularization of the placenta (By similarity). Involved in the immune response to infection by the bacteria S.aureus, S.typhimurium or S.enterica: infection promotes itaconate production, leading to alkylation, resulting in nuclear localization and transcription factor activity (PubMed:35662396). Itaconate-mediated alkylation activates TFEB-dependent lysosomal biogenesis, facilitating the bacteria clearance during the antibacterial innate immune response (PubMed:35662396).[UniProtKB:Q9R210]<ref>PMID:1748288</ref> <ref>PMID:19556463</ref> <ref>PMID:2115126</ref> <ref>PMID:21617040</ref> <ref>PMID:22343943</ref> <ref>PMID:22576015</ref> <ref>PMID:22692423</ref> <ref>PMID:23434374</ref> <ref>PMID:27278822</ref> <ref>PMID:29146937</ref> <ref>PMID:30120233</ref> <ref>PMID:31672913</ref> <ref>PMID:35662396</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB.,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 Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2213670120. doi: , 10.1073/pnas.2213670120. Epub 2023 Feb 7. PMID:36749723<ref>PMID:36749723</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7y62" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fang P]]
[[Category: Li P]]
[[Category: Lin Y]]
[[Category: Liu Z]]
[[Category: Sun H]]
[[Category: Wang J]]
[[Category: Yang G]]
[[Category: Zhao Z]]