| Structural highlights
3dtc 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.
| | Ligands: | ,
| | Gene: | MAP3K9, MLK1, PRKE1 (Homo sapiens) |
| Activity: | Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[M3K9_HUMAN] May play a role in esophageal cancer susceptibility and/or development.
Function
[M3K9_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. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Plays also a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.
Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.,Hudkins RL, Diebold JL, Tao M, Josef KA, Park CH, Angeles TS, Aimone LD, Husten J, Ator MA, Meyer SL, Holskin BP, Durkin JT, Fedorov AA, Fedorov EV, Almo SC, Mathiasen JR, Bozyczko-Coyne D, Saporito MS, Scott RW, Mallamo JP J Med Chem. 2008 Sep 25;51(18):5680-9. Epub 2008 Aug 21. PMID:18714982[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Durkin JT, Holskin BP, Kopec KK, Reed MS, Spais CM, Steffy BM, Gessner G, Angeles TS, Pohl J, Ator MA, Meyer SL. Phosphoregulation of mixed-lineage kinase 1 activity by multiple phosphorylation in the activation loop. Biochemistry. 2004 Dec 28;43(51):16348-55. PMID:15610029 doi:http://dx.doi.org/10.1021/bi049866y
- ↑ Xu Z, Maroney AC, Dobrzanski P, Kukekov NV, Greene LA. The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol Cell Biol. 2001 Jul;21(14):4713-24. PMID:11416147 doi:http://dx.doi.org/10.1128/MCB.21.14.4713-4724.2001
- ↑ Chen J, Guo L, Peiffer DA, Zhou L, Chan OT, Bibikova M, Wickham-Garcia E, Lu SH, Zhan Q, Wang-Rodriguez J, Jiang W, Fan JB. Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues. Int J Cancer. 2008 May 15;122(10):2249-54. doi: 10.1002/ijc.23397. PMID:18241037 doi:http://dx.doi.org/10.1002/ijc.23397
- ↑ Hudkins RL, Diebold JL, Tao M, Josef KA, Park CH, Angeles TS, Aimone LD, Husten J, Ator MA, Meyer SL, Holskin BP, Durkin JT, Fedorov AA, Fedorov EV, Almo SC, Mathiasen JR, Bozyczko-Coyne D, Saporito MS, Scott RW, Mallamo JP. Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. J Med Chem. 2008 Sep 25;51(18):5680-9. Epub 2008 Aug 21. PMID:18714982 doi:10.1021/jm8005838
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