6nuq | pdb_00006nuq

Stat3 Core in complex with compound SI109

Structural highlights

6nuq is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.15Å
Ligands:	KQV
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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.

Function

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]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy.

A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo.,Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, Chen J, Yang CY, Liu Z, Wang M, Liu L, Jiang H, Wen B, Kumar P, Meagher JL, Sun D, Stuckey JA, Wang S Cancer Cell. 2019 Nov 11;36(5):498-511.e17. doi: 10.1016/j.ccell.2019.10.002. PMID:31715132^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tsai YT, Su YH, Fang SS, Huang TN, Qiu Y, Jou YS, Shih HM, Kung HJ, Chen RH. Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation. Mol Cell Biol. 2000 Mar;20(6):2043-54. PMID:10688651
↑ Yamamoto T, Sekine Y, Kashima K, Kubota A, Sato N, Aoki N, Matsuda T. The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochem Biophys Res Commun. 2002 Oct 4;297(4):811-7. doi:, 10.1016/s0006-291x(02)02291-x. PMID:12359225 doi:https://dx.doi.org/10.1016/s0006-291x(02)02291-x
↑ Shao H, Cheng HY, Cook RG, Tweardy DJ. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res. 2003 Jul 15;63(14):3923-30. PMID:12873986
↑ Dreuw A, Radtke S, Pflanz S, Lippok BE, Heinrich PC, Hermanns HM. Characterization of the signaling capacities of the novel gp130-like cytokine receptor. J Biol Chem. 2004 Aug 20;279(34):36112-20. Epub 2004 Jun 11. PMID:15194700 doi:https://dx.doi.org/10.1074/jbc.M401122200
↑ Saxena NK, Vertino PM, Anania FA, Sharma D. leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. J Biol Chem. 2007 May 4;282(18):13316-25. doi: 10.1074/jbc.M609798200. Epub 2007 , Mar 7. PMID:17344214 doi:https://dx.doi.org/10.1074/jbc.M609798200
↑ Jiang H, Yu J, Guo H, Song H, Chen S. Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem Biophys Res Commun. 2008 Mar 28;368(1):1-5. doi:, 10.1016/j.bbrc.2007.04.004. Epub 2007 Sep 14. PMID:18242580 doi:https://dx.doi.org/10.1016/j.bbrc.2007.04.004
↑ Shen S, Niso-Santano M, Adjemian S, Takehara T, Malik SA, Minoux H, Souquere S, Marino G, Lachkar S, Senovilla L, Galluzzi L, Kepp O, Pierron G, Maiuri MC, Hikita H, Kroemer R, Kroemer G. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol Cell. 2012 Dec 14;48(5):667-80. doi: 10.1016/j.molcel.2012.09.013. Epub 2012 , Oct 17. PMID:23084476 doi:https://dx.doi.org/10.1016/j.molcel.2012.09.013
↑ Ma L, Huang C, Wang XJ, Xin DE, Wang LS, Zou QC, Zhang YS, Tan MD, Wang YM, Zhao TC, Chatterjee D, Altura RA, Wang C, Xu YS, Yang JH, Fan YS, Han BH, Si J, Zhang X, Cheng J, Chang Z, Chin YE. Lysyl Oxidase 3 Is a Dual-Specificity Enzyme Involved in STAT3 Deacetylation and Deacetylimination Modulation. Mol Cell. 2017 Jan 19;65(2):296-309. doi: 10.1016/j.molcel.2016.12.002. Epub 2017, Jan 5. PMID:28065600 doi:https://dx.doi.org/10.1016/j.molcel.2016.12.002
↑ Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, Chen J, Yang CY, Liu Z, Wang M, Liu L, Jiang H, Wen B, Kumar P, Meagher JL, Sun D, Stuckey JA, Wang S. A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo. Cancer Cell. 2019 Nov 11;36(5):498-511.e17. doi: 10.1016/j.ccell.2019.10.002. PMID:31715132 doi:https://dx.doi.org/10.1016/j.ccell.2019.10.002

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OCA

[1] Tsai YT, Su YH, Fang SS, Huang TN, Qiu Y, Jou YS, Shih HM, Kung HJ, Chen RH. Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation. Mol Cell Biol. 2000 Mar;20(6):2043-54. PMID:10688651

[2] Yamamoto T, Sekine Y, Kashima K, Kubota A, Sato N, Aoki N, Matsuda T. The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochem Biophys Res Commun. 2002 Oct 4;297(4):811-7. doi:, 10.1016/s0006-291x(02)02291-x. PMID:12359225 doi:https://dx.doi.org/10.1016/s0006-291x(02)02291-x

[3] Shao H, Cheng HY, Cook RG, Tweardy DJ. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res. 2003 Jul 15;63(14):3923-30. PMID:12873986

[4] Dreuw A, Radtke S, Pflanz S, Lippok BE, Heinrich PC, Hermanns HM. Characterization of the signaling capacities of the novel gp130-like cytokine receptor. J Biol Chem. 2004 Aug 20;279(34):36112-20. Epub 2004 Jun 11. PMID:15194700 doi:https://dx.doi.org/10.1074/jbc.M401122200

[5] Saxena NK, Vertino PM, Anania FA, Sharma D. leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. J Biol Chem. 2007 May 4;282(18):13316-25. doi: 10.1074/jbc.M609798200. Epub 2007 , Mar 7. PMID:17344214 doi:https://dx.doi.org/10.1074/jbc.M609798200

[6] Jiang H, Yu J, Guo H, Song H, Chen S. Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem Biophys Res Commun. 2008 Mar 28;368(1):1-5. doi:, 10.1016/j.bbrc.2007.04.004. Epub 2007 Sep 14. PMID:18242580 doi:https://dx.doi.org/10.1016/j.bbrc.2007.04.004

[7] Shen S, Niso-Santano M, Adjemian S, Takehara T, Malik SA, Minoux H, Souquere S, Marino G, Lachkar S, Senovilla L, Galluzzi L, Kepp O, Pierron G, Maiuri MC, Hikita H, Kroemer R, Kroemer G. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol Cell. 2012 Dec 14;48(5):667-80. doi: 10.1016/j.molcel.2012.09.013. Epub 2012 , Oct 17. PMID:23084476 doi:https://dx.doi.org/10.1016/j.molcel.2012.09.013

[8] Ma L, Huang C, Wang XJ, Xin DE, Wang LS, Zou QC, Zhang YS, Tan MD, Wang YM, Zhao TC, Chatterjee D, Altura RA, Wang C, Xu YS, Yang JH, Fan YS, Han BH, Si J, Zhang X, Cheng J, Chang Z, Chin YE. Lysyl Oxidase 3 Is a Dual-Specificity Enzyme Involved in STAT3 Deacetylation and Deacetylimination Modulation. Mol Cell. 2017 Jan 19;65(2):296-309. doi: 10.1016/j.molcel.2016.12.002. Epub 2017, Jan 5. PMID:28065600 doi:https://dx.doi.org/10.1016/j.molcel.2016.12.002

[9] Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, Chen J, Yang CY, Liu Z, Wang M, Liu L, Jiang H, Wen B, Kumar P, Meagher JL, Sun D, Stuckey JA, Wang S. A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo. Cancer Cell. 2019 Nov 11;36(5):498-511.e17. doi: 10.1016/j.ccell.2019.10.002. PMID:31715132 doi:https://dx.doi.org/10.1016/j.ccell.2019.10.002

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6nuq | pdb_00006nuq

Stat3 Core in complex with compound SI109

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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