6o94

Structure of the IRAK4 kinase domain with compound 17

spinqualitylabelsall models 6o94, resolution 1.98Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6o94 is a 4 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 1.98Å Ligands: CA, LRS, SEP, 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 series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model. Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.,Bryan MC, Drobnick J, Gobbi A, Kolesnikov A, Chen Y, Rajapaksa N, Ndubaku C, Feng J, Chang W, Francis R, Yu C, Choo EF, DeMent K, Ran Y, An L, Emson C, Huang Z, Sujatha-Bhaskar S, Brightbill H, DiPasquale A, Maher J, Wai J, McKenzie BS, Lupardus PJ, Zarrin AA, Kiefer JR J Med Chem. 2019 May 24. doi: 10.1021/acs.jmedchem.9b00439. PMID:31082230 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Interleukin-1 receptor-associated kinase

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