5j9l | pdb_00005j9l

Crystal structure of CPT1691 bound to TAK1-TAB1

Structural highlights

5j9l 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 2.7515Å
Ligands:	6HF
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TAB1_HUMAN May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.^[1] M3K7_HUMAN Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity.^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

TAK1 (transforming growth factor-beta-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.

Structure-guided development of covalent TAK1 inhibitors.,Tan L, Gurbani D, Weisberg EL, Hunter JC, Li L, Jones DS, Ficarro SB, Mowafy S, Tam CP, Rao S, Du G, Griffin JD, Sorger PK, Marto JA, Westover KD, Gray NS Bioorg Med Chem. 2017 Feb 1;25(3):838-846. doi: 10.1016/j.bmc.2016.11.035. Epub, 2016 Dec 9. PMID:28011204^[10]

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

References

↑ Conner SH, Kular G, Peggie M, Shepherd S, Schuttelkopf AW, Cohen P, Van Aalten DM. TAK1-binding protein 1 is a pseudophosphatase. Biochem J. 2006 Nov 1;399(3):427-34. PMID:16879102 doi:10.1042/BJ20061077
↑ Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E, Hagiwara M. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem. 1996 Jun 7;271(23):13675-9. PMID:8663074
↑ Shirakabe K, Yamaguchi K, Shibuya H, Irie K, Matsuda S, Moriguchi T, Gotoh Y, Matsumoto K, Nishida E. TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem. 1997 Mar 28;272(13):8141-4. PMID:9079627
↑ Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K. The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature. 1999 Mar 18;398(6724):252-6. PMID:10094049 doi:10.1038/18465
↑ Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001 Jul 19;412(6844):346-51. PMID:11460167 doi:10.1038/35085597
↑ Edlund S, Bu S, Schuster N, Aspenstrom P, Heuchel R, Heldin NE, ten Dijke P, Heldin CH, Landstrom M. Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell. 2003 Feb;14(2):529-44. PMID:12589052 doi:10.1091/mbc.02-03-0037
↑ Thiefes A, Wolf A, Doerrie A, Grassl GA, Matsumoto K, Autenrieth I, Bohn E, Sakurai H, Niedenthal R, Resch K, Kracht M. The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway. EMBO Rep. 2006 Aug;7(8):838-44. Epub 2006 Jul 14. PMID:16845370 doi:10.1038/sj.embor.7400754
↑ Huangfu WC, Omori E, Akira S, Matsumoto K, Ninomiya-Tsuji J. Osmotic stress activates the TAK1-JNK pathway while blocking TAK1-mediated NF-kappaB activation: TAO2 regulates TAK1 pathways. J Biol Chem. 2006 Sep 29;281(39):28802-10. Epub 2006 Aug 7. PMID:16893890 doi:10.1074/jbc.M603627200
↑ Pertel T, Hausmann S, Morger D, Zuger S, Guerra J, Lascano J, Reinhard C, Santoni FA, Uchil PD, Chatel L, Bisiaux A, Albert ML, Strambio-De-Castillia C, Mothes W, Pizzato M, Grutter MG, Luban J. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature. 2011 Apr 21;472(7343):361-5. doi: 10.1038/nature09976. PMID:21512573 doi:10.1038/nature09976
↑ Tan L, Gurbani D, Weisberg EL, Hunter JC, Li L, Jones DS, Ficarro SB, Mowafy S, Tam CP, Rao S, Du G, Griffin JD, Sorger PK, Marto JA, Westover KD, Gray NS. Structure-guided development of covalent TAK1 inhibitors. Bioorg Med Chem. 2017 Feb 1;25(3):838-846. doi: 10.1016/j.bmc.2016.11.035. Epub, 2016 Dec 9. PMID:28011204 doi:https://dx.doi.org/10.1016/j.bmc.2016.11.035

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OCA

[1] Conner SH, Kular G, Peggie M, Shepherd S, Schuttelkopf AW, Cohen P, Van Aalten DM. TAK1-binding protein 1 is a pseudophosphatase. Biochem J. 2006 Nov 1;399(3):427-34. PMID:16879102 doi:10.1042/BJ20061077

[2] Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E, Hagiwara M. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem. 1996 Jun 7;271(23):13675-9. PMID:8663074

[3] Shirakabe K, Yamaguchi K, Shibuya H, Irie K, Matsuda S, Moriguchi T, Gotoh Y, Matsumoto K, Nishida E. TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem. 1997 Mar 28;272(13):8141-4. PMID:9079627

[4] Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K. The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature. 1999 Mar 18;398(6724):252-6. PMID:10094049 doi:10.1038/18465

[5] Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001 Jul 19;412(6844):346-51. PMID:11460167 doi:10.1038/35085597

[6] Edlund S, Bu S, Schuster N, Aspenstrom P, Heuchel R, Heldin NE, ten Dijke P, Heldin CH, Landstrom M. Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell. 2003 Feb;14(2):529-44. PMID:12589052 doi:10.1091/mbc.02-03-0037

[7] Thiefes A, Wolf A, Doerrie A, Grassl GA, Matsumoto K, Autenrieth I, Bohn E, Sakurai H, Niedenthal R, Resch K, Kracht M. The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway. EMBO Rep. 2006 Aug;7(8):838-44. Epub 2006 Jul 14. PMID:16845370 doi:10.1038/sj.embor.7400754

[8] Huangfu WC, Omori E, Akira S, Matsumoto K, Ninomiya-Tsuji J. Osmotic stress activates the TAK1-JNK pathway while blocking TAK1-mediated NF-kappaB activation: TAO2 regulates TAK1 pathways. J Biol Chem. 2006 Sep 29;281(39):28802-10. Epub 2006 Aug 7. PMID:16893890 doi:10.1074/jbc.M603627200

[9] Pertel T, Hausmann S, Morger D, Zuger S, Guerra J, Lascano J, Reinhard C, Santoni FA, Uchil PD, Chatel L, Bisiaux A, Albert ML, Strambio-De-Castillia C, Mothes W, Pizzato M, Grutter MG, Luban J. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature. 2011 Apr 21;472(7343):361-5. doi: 10.1038/nature09976. PMID:21512573 doi:10.1038/nature09976

[10] Tan L, Gurbani D, Weisberg EL, Hunter JC, Li L, Jones DS, Ficarro SB, Mowafy S, Tam CP, Rao S, Du G, Griffin JD, Sorger PK, Marto JA, Westover KD, Gray NS. Structure-guided development of covalent TAK1 inhibitors. Bioorg Med Chem. 2017 Feb 1;25(3):838-846. doi: 10.1016/j.bmc.2016.11.035. Epub, 2016 Dec 9. PMID:28011204 doi:https://dx.doi.org/10.1016/j.bmc.2016.11.035

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5j9l | pdb_00005j9l

Crystal structure of CPT1691 bound to TAK1-TAB1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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