9DH3

Cryo-EM structure of NLRP3 complex with Compound C

This is a non-PDB format compatible entry.

Summary for 9DH3

• Entry DOI: 10.2210/pdb9dh3/pdb
• EMDB information: 46855
• Descriptor: Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera, ADENOSINE-5'-DIPHOSPHATE, 2-[(4S)-5-ethyl-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl]-N-(pyrimidin-4-yl)acetamide, ... (4 entities in total)
• Functional Keywords: nlrp3 inflammasome, small molecule inhibitors, and drug discovery, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 576936.92

Authors

Matico, R.,Grauwen, K.,Van Gool, M.,Muratore, E.M.,Yu, X.,Abdiaj, I.,Adhikary, S.,Adriaensen, I.,Aranzazu, G.M.,Alcazar, J.,Bassi, M.,Brisse, E.,Canellas, S.,Chaudhuri, S.,Chauhan, D.,Delgado, F.,Dieguez-Vazquez, A.,Du Jardin, M.,Eastham, V.,Finley, M.,Jacobs, T.,Keustermans, K.,Kuhn, R.,Llaveria, J.,Leenaerts, J.,Linares, M.L.,Martin, M.L.,Martinez, C.,Miller, R.,Munoz, F.M.,Nooyens, A.,Perez, L.B.,Perrier, M.,Pietrak, B.,Serre, J.,Sharma, S.,Somers, M.,Suarez, J.,Tresadern, G.,Trabanco, A.A.,Van den Bulck, D.,Van Hauwermeiren, F.,Varghese, T.,Vega, J.A.,Youssef, S.A.,Edwards, M.J.,Oehlrich, D.,Van Opdenbosch, N. (deposition date: 2024-09-03, release date: 2024-12-25, Last modification date: 2025-01-22)

Primary citation

Matico, R.,Grauwen, K.,Chauhan, D.,Yu, X.,Abdiaj, I.,Adhikary, S.,Adriaensen, I.,Aranzazu, G.M.,Alcazar, J.,Bassi, M.,Brisse, E.,Canellas, S.,Chaudhuri, S.,Delgado, F.,Dieguez-Vazquez, A.,Du Jardin, M.,Eastham, V.,Finley, M.,Jacobs, T.,Keustermans, K.,Kuhn, R.,Llaveria, J.,Leenaerts, J.,Linares, M.L.,Martin, M.L.,Martin-Perez, R.,Martinez, C.,Miller, R.,Munoz, F.M.,Muratore, M.E.,Nooyens, A.,Perez-Benito, L.,Perrier, M.,Pietrak, B.,Serre, J.,Sharma, S.,Somers, M.,Suarez, J.,Tresadern, G.,Trabanco, A.A.,Van den Bulck, D.,Van Gool, M.,Van Hauwermeiren, F.,Varghese, T.,Vega, J.A.,Youssef, S.A.,Edwards, M.J.,Oehlrich, D.,Van Opdenbosch, N.
Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome.
Embo Mol Med, 17:54-84, 2025

PubMed Abstract: The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical significance of modulating NLRP3. In this study, we present the identification of a novel chemical class exhibiting selective and potent inhibition of the NLRP3 inflammasome. Through a comprehensive structure-activity relationship (SAR) campaign, we optimized the lead molecule, compound A, for in vivo applications. Extensive in vitro and in vivo characterization of compound A confirmed the high selectivity and potency positioning compound A as a promising clinical candidate for diseases associated with aberrant NLRP3 activity. This research contributes to the ongoing efforts in developing targeted therapies for conditions involving NLRP3-mediated inflammation, opening avenues for further preclinical and clinical investigations.

PubMed: 39653810
DOI: 10.1038/s44321-024-00181-4

Experimental method

ELECTRON MICROSCOPY (3.76 Å)