4DKD

Crystal Structure of Human Interleukin-34 Bound to Human CSF-1R

Summary for 4DKD

• Entry DOI: 10.2210/pdb4dkd/pdb
• Descriptor: Interleukin-34, Macrophage colony-stimulating factor 1 receptor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: dimeric four-helix bundle cytokine, receptor tyrosine kinase, glycosylation, cytokine-transferase complex, cytokine/transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 77006.20

Authors

Ma, X.,Bazan, J.F.,Starovasnik, M.A. (deposition date: 2012-02-03, release date: 2012-04-11, Last modification date: 2020-07-29)

Primary citation

Ma, X.,Lin, W.Y.,Chen, Y.,Stawicki, S.,Mukhyala, K.,Wu, Y.,Martin, F.,Bazan, J.F.,Starovasnik, M.A.
Structural Basis for the Dual Recognition of Helical Cytokines IL-34 and CSF-1 by CSF-1R.
Structure, 20:676-687, 2012

PubMed Abstract: Lacking any discernible sequence similarity, interleukin-34 (IL-34) and colony stimulating factor 1 (CSF-1) signal through a common receptor CSF-1R on cells of mononuclear phagocyte lineage. Here, the crystal structure of dimeric IL-34 reveals a helical cytokine fold homologous to CSF-1, and we further show that the complex architecture of IL-34 bound to the N-terminal immunoglobulin domains of CSF-1R is similar to the CSF-1/CSF-1R assembly. However, unique conformational adaptations in the receptor domain geometry and intermolecular interface explain the cross-reactivity of CSF-1R for two such distantly related ligands. The docking adaptations of the IL-34 and CSF-1 quaternary complexes, when compared to the stem cell factor assembly, draw a common evolutionary theme for transmembrane signaling. In addition, the structure of IL-34 engaged by a Fab fragment reveals the mechanism of a neutralizing antibody that can help deconvolute IL-34 from CSF-1 biology, with implications for therapeutic intervention in diseases with myeloid pathogenic mechanisms.

PubMed: 22483114
DOI: 10.1016/j.str.2012.02.010

Experimental method

X-RAY DIFFRACTION (3 Å)