| Structural highlights
6yox is a 2 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 2.05Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
TF65_HUMAN NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Small-molecule stabilization of protein-protein interactions (PPI) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a 'bottom-up' approach is largely unanswered. Here we report a novel concept for identifying initial chemical matter for PPI stabilization based on covalent imine forming fragments. The imine bond offers a covalent anchor for site-directed fragment targeting, whereas its transient nature allows an efficient structure activity relationship analysis. This bond enables fragment identification and optimisation using protein crystallography. We report novel fragments which bind specifically to a lysine at the PPI interface of the p65 subunit-derived peptide of NF-kappaB with the adapter protein 14-3-3. Those fragments that subsequently establish contacts with the p65-derived peptide, rather than with 14-3-3, efficiently stabilize the 14-3-3/p65 complex and offer novel starting points for molecular glues.
Fragment Based Protein-Protein Interaction Stabilizers via Imine-Based Tethering.,Ottmann C, Wolter M, Valenti D, Cossar PJ, Levy LM, Hristeva S, Genski T, Hoffmann T, Brunsveld L, Tzalis D Angew Chem Int Ed Engl. 2020 Aug 20. doi: 10.1002/anie.202008585. PMID:32816380[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schulte R, Grassl GA, Preger S, Fessele S, Jacobi CA, Schaller M, Nelson PJ, Autenrieth IB. Yersinia enterocolitica invasin protein triggers IL-8 production in epithelial cells via activation of Rel p65-p65 homodimers. FASEB J. 2000 Aug;14(11):1471-84. PMID:10928981
- ↑ Asamitsu K, Tetsuka T, Kanazawa S, Okamoto T. RING finger protein AO7 supports NF-kappaB-mediated transcription by interacting with the transactivation domain of the p65 subunit. J Biol Chem. 2003 Jul 18;278(29):26879-87. Epub 2003 May 13. PMID:12748188 doi:10.1074/jbc.M211831200
- ↑ Liu Y, Smith PW, Jones DR. Breast cancer metastasis suppressor 1 functions as a corepressor by enhancing histone deacetylase 1-mediated deacetylation of RelA/p65 and promoting apoptosis. Mol Cell Biol. 2006 Dec;26(23):8683-96. Epub 2006 Sep 25. PMID:17000776 doi:10.1128/MCB.00940-06
- ↑ Sun S, Tang Y, Lou X, Zhu L, Yang K, Zhang B, Shi H, Wang C. UXT is a novel and essential cofactor in the NF-kappaB transcriptional enhanceosome. J Cell Biol. 2007 Jul 16;178(2):231-44. Epub 2007 Jul 9. PMID:17620405 doi:jcb.200611081
- ↑ Ishaq M, Ma L, Wu X, Mu Y, Pan J, Hu J, Hu T, Fu Q, Guo D. The DEAD-box RNA helicase DDX1 interacts with RelA and enhances nuclear factor kappaB-mediated transcription. J Cell Biochem. 2009 Feb 1;106(2):296-305. doi: 10.1002/jcb.22004. PMID:19058135 doi:10.1002/jcb.22004
- ↑ Sharif-Askari E, Vassen L, Kosan C, Khandanpour C, Gaudreau MC, Heyd F, Okayama T, Jin J, Rojas ME, Grimes HL, Zeng H, Moroy T. Zinc finger protein Gfi1 controls the endotoxin-mediated Toll-like receptor inflammatory response by antagonizing NF-kappaB p65. Mol Cell Biol. 2010 Aug;30(16):3929-42. doi: 10.1128/MCB.00087-10. Epub 2010 Jun , 14. PMID:20547752 doi:10.1128/MCB.00087-10
- ↑ Wolter M, Valenti D, Cossar PJ, Levy LM, Hristeva S, Genski T, Hoffmann T, Brunsveld L, Tzalis D, Ottmann C. Fragment-Based Stabilizers of Protein-Protein Interactions through Imine-Based Tethering. Angew Chem Int Ed Engl. 2020 Nov 23;59(48):21520-21524. PMID:32816380 doi:10.1002/anie.202008585
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