6NPY

Cryo-EM structure of NLRP3 bound to NEK7

Summary for 6NPY

• Entry DOI: 10.2210/pdb6npy/pdb
• EMDB information: 0476
• Descriptor: NACHT, LRR and PYD domains-containing protein 3, Protein kinase R,Serine/threonine-protein kinase Nek7, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: inflammasome, activator, biological process immunity, inflammatory response, innate immunity, transcription, transcription regulation ligand, atp binding, nucleotide binding, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 150333.33

Authors

Sharif, H.,Wang, L.,Wang, W.L.,Wu, H. (deposition date: 2019-01-18, release date: 2019-06-19, Last modification date: 2024-03-20)

Primary citation

Sharif, H.,Wang, L.,Wang, W.L.,Magupalli, V.G.,Andreeva, L.,Qiao, Q.,Hauenstein, A.V.,Wu, Z.,Nunez, G.,Mao, Y.,Wu, H.
Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome.
Nature, 570:338-343, 2019

PubMed Abstract: The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-β fibrils and extracellular ATP. The mitotic kinase NEK7 licenses the assembly and activation of the NLRP3 inflammasome in interphase. Here we report a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7, at a resolution of 3.8 Å. The earring-shaped NLRP3 consists of curved leucine-rich-repeat and globular NACHT domains, and the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells. Modelling of an active NLRP3-NEK7 conformation based on the NLRC4 inflammasome predicts an additional contact between an NLRP3-bound NEK7 and a neighbouring NLRP3. Mutations to this interface abolish the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome.

PubMed: 31189953
DOI: 10.1038/s41586-019-1295-z

Experimental method

ELECTRON MICROSCOPY (3.8 Å)