9pss

IRAK4 in Complex with Compound 3

spinqualitylabelsall models 9pss, resolution 1.93Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9pss 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 1.93Å Ligands: A1CKP, SEP, SO4, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease IRAK4_HUMAN Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:610799. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD. Defects in IRAK4 are the cause of IRAK4 deficiency (IRAK4D) [MIM:607676. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. Function IRAK4_HUMAN Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. Publication Abstract from PubMed A hallmark of most known small-molecule orthosteric kinase inhibitors is hydrogen-bonding to the hinge-region of the kinase to mimic the hinge interaction of adenine. Herein we report our studies on deviation from canonical hinge-binders in the context of IRAK4 inhibitors. Small-molecule inhibitors of IRAK4 have generated interest as potential treatments for inflammatory diseases. Notably, in our discovery efforts we identified pyridinyl-thiadiazoles as noncanonical hinge-binders. X-ray structural evidence supports that the thiadiazole moiety engages in a rare intermolecular noncovalent sulfur-oxygen interaction. This thiadiazole series, exemplified by compounds 19 and 22, has shown promise for potent, selective, orally bioavailable IRAK4 inhibitors. Examination of Noncanonical Kinase Hinge Binders Leads to Thiadiazoles as Potent IRAK4 Inhibitors.,Ammann SE, Brizgys G, Ferrao RD, Wright NE, Mukherjee PK, Bacon EM, Chin E, Chou C, Cottell JJ, Hammond A, Ndukwe MS, Park GY, Shatskikh ME, Suekawa-Pirrone K, Warr MR, Yang ZY, Zipfel SM, Taylor JG ACS Med Chem Lett. 2025 Dec 16;17(1):175-182. doi: , 10.1021/acsmedchemlett.5c00602. eCollection 2026 Jan 8. PMID:41531974 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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