9J4P
Regulatory domain and kinase domain of ALPK1 protein
Summary for 9J4P
| Entry DOI | 10.2210/pdb9j4p/pdb |
| Descriptor | Alpha-protein kinase 1, [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2S,3S,4S,5S,6R)-6-[(1R)-1,2-bis(oxidanyl)ethyl]-3,4,5-tris(oxidanyl)oxan-2-yl] hydrogen phosphate, ZINC ION, ... (5 entities in total) |
| Functional Keywords | complex, kinase, immunity, antiviral protein |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 2 |
| Total formula weight | 82383.21 |
| Authors | |
| Primary citation | Fan, J.,Liu, D.,Ming, Z.,Yan, C.,Dang, H.,Pan, Y.,Wei, X.,Zhao, Z.,Wang, W.,Zhang, S.,Chen, L.,Cai, S.,Ke, J.,Luo, Y.,Rao, L.,Chen, J.,Chen, Z.,Zhou, J.,Chen, F.,Duan, X.,Ren, B.,Li, T.R.,Melvin, L.,Yogaratnam, J.,Mahajan, V.B.,Song, H.,Lichenstein, H.,Xu, T.,Xu, C. Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome. Nat Commun, 16:8251-8251, 2025 Cited by PubMed Abstract: ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome is a rare genetic disease caused by variants in alpha-kinase 1 (ALPK1) resulting in downstream pro-inflammatory signaling mediated by the TIFA/TRAF6/NF-κB pathway. Here, we report the design of an ALPK1 inhibitor, DF-003, with pharmacokinetic properties suitable for daily oral dosing. In biochemical assays, DF-003 potently inhibits human ALPK1 (IC = 1.5 nM) and the ROSAH disease-causing mutant ALPK1[T237M] (IC = 16 nM). When tested against a panel of 394 human kinases, DF-003 exhibits ≥860-fold selectivity over the closest kinase. In cell-based assays, DF-003 suppresses inflammatory cytokine signaling mediated both by wild-type ALPK1 and the disease-causing ALPK1[T237M] mutant. Using mice heterozygous for wild-type human ALPK1 and ALPK1 established to model ROSAH syndrome that exhibit retinal microglial infiltration, astrocyte activation, and inflammatory cytokine upregulation in the retina, optic nerve, and cortex, we show that orally administered DF-003 is sufficient to inhibit these inflammatory phenotypes. PubMed: 40925900DOI: 10.1038/s41467-025-63731-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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