6tlc

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Current revision (13:04, 24 January 2024) (edit) (undo)
 
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==Unphosphorylated human STAT3 in complex with MS3-6 monobody==
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<StructureSection load='6tlc' size='340' side='right'caption='[[6tlc]]' scene=''>
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<StructureSection load='6tlc' size='340' side='right'caption='[[6tlc]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6tlc]] is a 4 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=6TLC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TLC FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6tlc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tlc OCA], [http://pdbe.org/6tlc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tlc RCSB], [http://www.ebi.ac.uk/pdbsum/6tlc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tlc ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6tlc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tlc OCA], [https://pdbe.org/6tlc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tlc RCSB], [https://www.ebi.ac.uk/pdbsum/6tlc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tlc ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/STAT3_HUMAN STAT3_HUMAN] Chronic lymphoproliferative disorder of natural killer cells;Autosomal dominant hyper-IgE syndrome;STAT3-related early-onset multisystem autoimmune disease;T-cell large granular lymphocyte leukemia;Permanent neonatal diabetes mellitus. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
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== Function ==
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[https://www.uniprot.org/uniprot/STAT3_HUMAN STAT3_HUMAN] Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (PubMed:10688651, PubMed:12359225, PubMed:12873986, PubMed:15194700, PubMed:17344214, PubMed:18242580, PubMed:23084476). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:17344214). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:12873986). Binds to the interleukin-6 (IL-6)-responsive elements identified in the promoters of various acute-phase protein genes (PubMed:12359225). Activated by IL31 through IL31RA (PubMed:15194700). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity (PubMed:28065600). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (PubMed:23084476). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity).[UniProtKB:P42227]<ref>PMID:10688651</ref> <ref>PMID:12359225</ref> <ref>PMID:12873986</ref> <ref>PMID:15194700</ref> <ref>PMID:17344214</ref> <ref>PMID:18242580</ref> <ref>PMID:23084476</ref> <ref>PMID:28065600</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The transcription factor STAT3 is frequently activated in human solid and hematological malignancies and remains a challenging therapeutic target with no approved drugs to date. Here, we develop synthetic antibody mimetics, termed monobodies, to interfere with STAT3 signaling. These monobodies are highly selective for STAT3 and bind with nanomolar affinity to the N-terminal and coiled-coil domains. Interactome analysis detects no significant binding to other STATs or additional off-target proteins, confirming their exquisite specificity. Intracellular expression of monobodies fused to VHL, an E3 ubiquitin ligase substrate receptor, results in degradation of endogenous STAT3. The crystal structure of STAT3 in complex with monobody MS3-6 reveals bending of the coiled-coil domain, resulting in diminished DNA binding and nuclear translocation. MS3-6 expression strongly inhibits STAT3-dependent transcriptional activation and disrupts STAT3 interaction with the IL-22 receptor. Therefore, our study establishes innovative tools to interfere with STAT3 signaling by different molecular mechanisms.
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Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains.,La Sala G, Michiels C, Kukenshoner T, Brandstoetter T, Maurer B, Koide A, Lau K, Pojer F, Koide S, Sexl V, Dumoutier L, Hantschel O Nat Commun. 2020 Aug 17;11(1):4115. doi: 10.1038/s41467-020-17920-z. PMID:32807795<ref>PMID:32807795</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6tlc" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Z-disk]]
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[[Category: Hantschel O]]
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[[Category: La Sala G]]
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[[Category: Lau K]]
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[[Category: Pojer F]]
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[[Category: Reynaud A]]

Current revision

Unphosphorylated human STAT3 in complex with MS3-6 monobody

PDB ID 6tlc

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