6N33

Crystal structure of fms kinase domain with a small molecular inhibitor, PLX5622

6N33 の概要

• エントリーDOI: 10.2210/pdb6n33/pdb
• 分子名称: 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)
• 機能のキーワード: csf-1-r, fms proto-oncogene, c-fms, cd115 antigen, kinase, atp-binding, plx5622, transferase-transferase inhibitor complex, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39035.58

構造登録者

Zhang, Y. (登録日: 2018-11-14, 公開日: 2019-09-18, 最終更新日: 2023-10-11)

主引用文献

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

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: 31434879
DOI: 10.1038/s41467-019-11674-z

実験手法

X-RAY DIFFRACTION (2.25 Å)