2OGV

Crystal Structure of the Autoinhibited Human c-Fms Kinase Domain

2OGV の概要

• エントリーDOI: 10.2210/pdb2ogv/pdb
• 分子名称: Macrophage colony-stimulating factor 1 receptor precursor (2 entities in total)
• 機能のキーワード: receptor tyrosine kinase, macrophage colony stimulating factor receptor, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: P07333
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35791.06

構造登録者

Walter, M.,Lucet, I.S.,Patel, O.,Broughton, S.E.,Bamert, R.,Williams, N.K.,Fantino, E.,Wilks, A.F.,Rossjohn, J. (登録日: 2007-01-09, 公開日: 2007-02-06, 最終更新日: 2023-08-30)

主引用文献

Walter, M.,Lucet, I.S.,Patel, O.,Broughton, S.E.,Bamert, R.,Williams, N.K.,Fantino, E.,Wilks, A.F.,Rossjohn, J.
The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain.
J.Mol.Biol., 367:839-847, 2007

PubMed Abstract: c-Fms, a member of the Platelet-derived Growth Factor (PDGF) receptor family of receptor tyrosine kinases (RTKs), is the receptor for macrophage colony stimulating factor (CSF-1) that regulates proliferation, differentiation and survival of cells of the mononuclear phagocyte lineage. Abnormal expression of c-fms proto-oncogene is associated with a significant number of human pathologies, including a variety of cancers and rheumatoid arthritis. Accordingly, c-Fms represents an attractive therapeutic target. To further understand the regulation of c-Fms, we determined the 2.7 A resolution crystal structure of the cytosolic domain of c-Fms that comprised the kinase domain and the juxtamembrane domain. The structure reveals the crucial inhibitory role of the juxtamembrane domain (JM) that binds to a hydrophobic site immediately adjacent to the ATP binding pocket. This interaction prevents the activation loop from adopting an active conformation thereby locking the c-Fms kinase into an autoinhibited state. As observed for other members of the PDGF receptor family, namely c-Kit and Flt3, three JM-derived tyrosine residues primarily drive the mechanism for autoinhibition in c-Fms, therefore defining a common autoinhibitory mechanism within this family. Moreover the structure provides an understanding of c-Fms inhibition by Gleevec as well as providing a platform for the development of more selective inhibitors that target the inactive conformation of c-Fms kinase.

PubMed: 17292918
DOI: 10.1016/j.jmb.2007.01.036

実験手法

X-RAY DIFFRACTION (2.7 Å)