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The crystal structure of the catalytic domain of the NF-κB inducing kinase reveals a narrow but flexible active site.

de Leon-Boenig G, Bowman KK, Feng JA, Crawford T, Everett C, Franke Y, Oh A, Stanley M, Staben ST, Starovasnik MA, Wallweber HJ, Wu J, Wu LC, Johnson AR, Hymowitz SG
Structure 20 1704-14 (2012)
Related entries: 4g3c, 4g3d, 4g3e, 4g3g

Cited: 35 times
EuropePMC logo PMID: 22921830

Abstract

The NF-κB inducing kinase (NIK) regulates the non-canonical NF-κB pathway downstream of important clinical targets including BAFF, RANKL, and LTβ. Despite numerous genetic studies associating dysregulation of this pathway with autoimmune diseases and hematological cancers, detailed molecular characterization of this central signaling node has been lacking. We undertook a systematic cloning and expression effort to generate soluble, well-behaved proteins encompassing the kinase domains of human and murine NIK. Structures of the apo NIK kinase domain from both species reveal an active-like conformation in the absence of phosphorylation. ATP consumption and peptide phosphorylation assays confirm that phosphorylation of NIK does not increase enzymatic activity. Structures of murine NIK bound to inhibitors possessing two different chemotypes reveal conformational flexibility in the gatekeeper residue controlling access to a hydrophobic pocket. Finally, a single amino acid difference affects the ability of some inhibitors to bind murine and human NIK with the same affinity.

Reviews - 4g3f mentioned but not cited (1)

  1. Pharmacological inhibition of NF-κB-inducing kinase (NIK) with small molecules for the treatment of human diseases. Cheng J, Feng X, Li Z, Zhou F, Yang JM, Zhao Y. RSC Med Chem 12 552-565 (2021)

Articles - 4g3f mentioned but not cited (1)

  1. Curcumin Decreases Viability and Inhibits Proliferation of Imatinib-Sensitive and Imatinib-Resistant Chronic Myeloid Leukemia Cell Lines. Bilajac E, Mahmutović L, Glamočlija U, Osmanović A, Hromić-Jahjefendić A, Tambuwala MM, Suljagić M. Metabolites 13 58 (2022)


Reviews citing this publication (11)

  1. The non-canonical NF-κB pathway in immunity and inflammation. Sun SC. Nat Rev Immunol 17 545-558 (2017)
  2. The IκB kinase complex in NF-κB regulation and beyond. Hinz M, Scheidereit C. EMBO Rep 15 46-61 (2014)
  3. Regulation of nuclear factor-κB in autoimmunity. Sun SC, Chang JH, Jin J. Trends Immunol 34 282-289 (2013)
  4. Redox activation of Nrf2 & NF-κB: a double end sword? Buelna-Chontal M, Zazueta C. Cell Signal 25 2548-2557 (2013)
  5. Targeting NF-κB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer. Pflug KM, Sitcheran R. Int J Mol Sci 21 E8470 (2020)
  6. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting. Jonckheere N, Vasseur R, Van Seuningen I. Crit Rev Oncol Hematol 111 7-19 (2017)
  7. Non-Canonical NF-κB Signaling Initiated by BAFF Influences B Cell Biology at Multiple Junctures. Gardam S, Brink R. Front Immunol 4 509 (2014)
  8. Unlocking the NF-κB Conundrum: Embracing Complexity to Achieve Specificity. Begalli F, Bennett J, Capece D, Verzella D, D'Andrea D, Tornatore L, Franzoso G. Biomedicines 5 E50 (2017)
  9. Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets. Paul A, Edwards J, Pepper C, Mackay S. Cells 7 E176 (2018)
  10. RIPK protein kinase family: Atypical lives of typical kinases. Cuny GD, Degterev A. Semin Cell Dev Biol 109 96-105 (2021)
  11. The Therapeutic Potential of Targeting NIK in B Cell Malignancies. Haselager MV, Eldering E. Front Immunol 13 930986 (2022)

Articles citing this publication (22)

  1. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Willmann KL, Klaver S, Doğu F, Santos-Valente E, Garncarz W, Bilic I, Mace E, Salzer E, Conde CD, Sic H, Májek P, Banerjee PP, Vladimer GI, Haskoloğlu S, Bolkent MG, Küpesiz A, Condino-Neto A, Colinge J, Superti-Furga G, Pickl WF, van Zelm MC, Eibel H, Orange JS, Ikincioğulları A, Boztuğ K. Nat Commun 5 5360 (2014)
  2. Inhibition of LTβR signalling activates WNT-induced regeneration in lung. Conlon TM, John-Schuster G, Heide D, Pfister D, Lehmann M, Hu Y, Ertüz Z, Lopez MA, Ansari M, Strunz M, Mayr C, Angelidis I, Ciminieri C, Costa R, Kohlhepp MS, Guillot A, Günes G, Jeridi A, Funk MC, Beroshvili G, Prokosch S, Hetzer J, Verleden SE, Alsafadi H, Lindner M, Burgstaller G, Becker L, Irmler M, Dudek M, Janzen J, Goffin E, Gosens R, Knolle P, Pirotte B, Stoeger T, Beckers J, Wagner D, Singh I, Theis FJ, de Angelis MH, O'Connor T, Tacke F, Boutros M, Dejardin E, Eickelberg O, Schiller HB, Königshoff M, Heikenwalder M, Yildirim AÖ. Nature 588 151-156 (2020)
  3. NF-κB-inducing kinase is a key regulator of inflammation-induced and tumour-associated angiogenesis. Noort AR, van Zoest KP, Weijers EM, Koolwijk P, Maracle CX, Novack DV, Siemerink MJ, Schlingemann RO, Tak PP, Tas SW. J Pathol 234 375-385 (2014)
  4. NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus. Brightbill HD, Suto E, Blaquiere N, Ramamoorthi N, Sujatha-Bhaskar S, Gogol EB, Castanedo GM, Jackson BT, Kwon YC, Haller S, Lesch J, Bents K, Everett C, Kohli PB, Linge S, Christian L, Barrett K, Jaochico A, Berezhkovskiy LM, Fan PW, Modrusan Z, Veliz K, Townsend MJ, DeVoss J, Johnson AR, Godemann R, Lee WP, Austin CD, McKenzie BS, Hackney JA, Crawford JJ, Staben ST, Alaoui Ismaili MH, Wu LC, Ghilardi N. Nat Commun 9 179 (2018)
  5. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury. Ren X, Li X, Jia L, Chen D, Hou H, Rui L, Zhao Y, Chen Z. FASEB J 31 711-718 (2017)
  6. Nuclear factor-κB-inducing kinase (NIK) contains an amino-terminal inhibitor of apoptosis (IAP)-binding motif (IBM) that potentiates NIK degradation by cellular IAP1 (c-IAP1). Lee S, Challa-Malladi M, Bratton SB, Wright CW. J Biol Chem 289 30680-30689 (2014)
  7. NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis. Boutaffala L, Bertrand MJ, Remouchamps C, Seleznik G, Reisinger F, Janas M, Bénézech C, Fernandes MT, Marchetti S, Mair F, Ganeff C, Hupalowska A, Ricci JE, Becher B, Piette J, Knolle P, Caamano J, Vandenabeele P, Heikenwalder M, Dejardin E. Cell Death Differ 22 2020-2033 (2015)
  8. Research Support, Non-U.S. Gov't Targeting the alternative NF-κB pathway in pancreatic cancer: a new direction for therapy? Storz P. Expert Rev Anticancer Ther 13 501-504 (2013)
  9. N-Acetyl-3-aminopyrazoles block the non-canonical NF-kB cascade by selectively inhibiting NIK. Pippione AC, Sainas S, Federico A, Lupino E, Piccinini M, Kubbutat M, Contreras JM, Morice C, Barge A, Ducime A, Boschi D, Al-Karadaghi S, Lolli ML. Medchemcomm 9 963-968 (2018)
  10. Nuclear Factor-κB-inducing Kinase Is Expressed in Synovial Endothelial Cells in Patients with Early Arthritis and Correlates with Markers of Inflammation: A Prospective Cohort Study. Maijer KI, Noort AR, de Hair MJ, van der Leij C, van Zoest KP, Choi IY, Gerlag DM, Maas M, Tak PP, Tas SW. J Rheumatol 42 1573-1581 (2015)
  11. Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice. Li X, Jia L, Chen X, Dong Y, Ren X, Dong Y, Chen Y, Xie L, Liu M, Shiota C, Gittes GK, Rui L, Chen Z. Theranostics 8 5960-5971 (2018)
  12. The Role of Ubiquitination in TWEAK-Stimulated Signaling. Vucic D. Front Immunol 4 472 (2013)
  13. The structure of Legionella pneumophila LegK4 type four secretion system (T4SS) effector reveals a novel dimeric eukaryotic-like kinase. Flayhan A, Bergé C, Baïlo N, Doublet P, Bayliss R, Terradot L. Sci Rep 5 14602 (2015)
  14. Discovering protein-ligand chalcogen bonding in the protein data bank using endocyclic sulfur-containing heterocycles as ligand search subsets. Mitchell MO. J Mol Model 23 287 (2017)
  15. Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors. Shen C, Liu H, Wang X, Lei T, Wang E, Xu L, Yu H, Li D, Yao X. Front Pharmacol 10 345 (2019)
  16. Therapeutic Potential of Standardized Extract of Melilotus indicus (L.) All. and Its Phytochemicals against Skin Cancer in Animal Model: In Vitro, In Vivo, and In Silico Studies. Bashir A, Asif M, Saadullah M, Saleem M, Khalid SH, Hussain L, Ullah Khan I, Sidra Yaseen H, Zubair HM, Shamas MU, Al Zarzour R, Chohan TA. ACS Omega 7 25772-25782 (2022)
  17. Primary structural features of SR-like protein acinusS govern the phosphorylation mechanism by SRPK2. Liang N, Zeng C, Tao KP, Sou WH, Hsia HP, Qu D, Lau SN, Ngo JC. Biochem J 459 181-191 (2014)
  18. Understanding NIK regulation from its structure. Tao Z, Ghosh G. Structure 20 1615-1617 (2012)
  19. Structure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1). Feng JA, Lee P, Alaoui MH, Barrett K, Castanedo G, Godemann R, McEwan P, Wang X, Wu P, Zhang Y, Harris SF, Staben ST. ACS Med Chem Lett 10 1260-1265 (2019)
  20. Inhibition of non-canonical NF-κB signaling suppresses periodontal inflammation and bone loss. Aoki T, Hiura F, Li A, Yang N, Takakura-Hino N, Mukai S, Matsuda M, Nishimura F, Jimi E. Front Immunol 14 1179007 (2023)
  21. D3PM: a comprehensive database for protein motions ranging from residue to domain. Peng C, Zhang X, Xu Z, Chen Z, Yang Y, Cai T, Zhu W. BMC Bioinformatics 23 70 (2022)
  22. Prediction of anticancer property of bowsellic acid derivatives by quantitative structure activity relationship analysis and molecular docking study. Satpathy R, Guru RK, Behera R, Nayak B. J Pharm Bioallied Sci 7 21-25 (2015)


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