6N33
Crystal structure of fms kinase domain with a small molecular inhibitor, PLX5622
Summary for 6N33
| Entry DOI | 10.2210/pdb6n33/pdb |
| Descriptor | Macrophage colony-stimulating factor 1 receptor, 6-fluoro-N-[(5-fluoro-2-methoxypyridin-3-yl)methyl]-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyridin-2-amine (3 entities in total) |
| Functional Keywords | csf-1-r, fms proto-oncogene, c-fms, cd115 antigen, kinase, atp-binding, plx5622, transferase-transferase inhibitor complex, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 39035.58 |
| Authors | Zhang, Y. (deposition date: 2018-11-14, release date: 2019-09-18, Last modification date: 2023-10-11) |
| Primary citation | Spangenberg, E.,Severson, P.L.,Hohsfield, L.A.,Crapser, J.,Zhang, J.,Burton, E.A.,Zhang, Y.,Spevak, W.,Lin, J.,Phan, N.Y.,Habets, G.,Rymar, A.,Tsang, G.,Walters, J.,Nespi, M.,Singh, P.,Broome, S.,Ibrahim, P.,Zhang, C.,Bollag, G.,West, B.L.,Green, K.N. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model. Nat Commun, 10:3758-3758, 2019 Cited by PubMed Abstract: Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis. PubMed: 31434879DOI: 10.1038/s41467-019-11674-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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