3EJJ

Structure of M-CSF bound to the first three domains of FMS

Summary for 3EJJ

• Entry DOI: 10.2210/pdb3ejj/pdb
• Descriptor: Colony stimulating factor-1, Macrophage colony-stimulating factor 1 receptor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: growth factor-receptor complex, receptor tyrosine kinase, cytokine, 4-helix bundle, atp-binding, glycoprotein, immunoglobulin domain, kinase, membrane, nucleotide-binding, phosphoprotein, proto-oncogene, receptor, transferase, transmembrane, tyrosine-protein kinase, cytokine-signaling protein complex, cytokine/signaling protein
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 3
• Total formula weight: 69289.66

Authors

Chen, X.,Liu, H.,Focia, P.J.,Shim, A.,He, X. (deposition date: 2008-09-18, release date: 2008-12-09, Last modification date: 2024-11-20)

Primary citation

Chen, X.,Liu, H.,Focia, P.J.,Shim, A.H.,He, X.
Structure of macrophage colony stimulating factor bound to FMS: diverse signaling assemblies of class III receptor tyrosine kinases.
Proc.Natl.Acad.Sci.USA, 105:18267-18272, 2008

PubMed Abstract: Macrophage colony stimulating factor (M-CSF), through binding to its receptor FMS, a class III receptor tyrosine kinase (RTK), regulates the development and function of mononuclear phagocytes, and plays important roles in innate immunity, cancer and inflammation. We report a 2.4 A crystal structure of M-CSF bound to the first 3 domains (D1-D3) of FMS. The ligand binding mode of FMS is surprisingly different from KIT, another class III RTK, in which the major ligand-binding domain of FMS, D2, uses the CD and EF loops, but not the beta-sheet on the opposite side of the Ig domain as in KIT, to bind ligand. Calorimetric data indicate that M-CSF cannot dimerize FMS without receptor-receptor interactions mediated by FMS domains D4 and D5. Consistently, the structure contains only 1 FMS-D1-D3 molecule bound to a M-CSF dimer, due to a weak, hydrophilic M-CSF:FMS interface, and probably a conformational change of the M-CSF dimer in which binding to the second site is rendered unfavorable by FMS binding at the first site. The partial, intermediate complex suggests that FMS may be activated in two steps, with the initial engagement step distinct from the subsequent dimerization/activation step. Hence, the formation of signaling class III RTK complexes can be diverse, engaging various modes of ligand recognition and various mechanistic steps for dimerizing and activating receptors.

PubMed: 19017797
DOI: 10.1073/pnas.0807762105

Experimental method

X-RAY DIFFRACTION (2.4 Å)