5DWU: Beta common receptor in complex with a Fab

Citation:
Abstract
The beta common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of haematopoietic cells via a receptor complex incorporating cytokine-specific alpha and shared beta common (betac, CD131) receptor. Evidence from animal models and recent clinical trials demonstrate that these cytokines are critical mediators of the pathogenesis of inflammatory airway disease such as asthma. However, no therapeutic agents, other than steroids, that specifically and effectively target inflammation mediated by all 3 of these cytokines exist. We employed phage display technology to identify and optimize a novel, human monoclonal antibody (CSL311) that binds to a unique epitope that is specific to the cytokine-binding site of the human betac receptor. The binding epitope of CSL311 on the betac receptor was defined by X-ray crystallography and site-directed mutagenesis. CSL311 has picomolar binding affinity for the human betac receptor, and at therapeutic concentrations is a highly potent antagonist of the combined activities of IL-3, GM-CSF and IL-5 on primary eosinophil survival in vitro. Importantly, CSL311 inhibited the survival of inflammatory cells present in induced sputum from human allergic asthmatic subjects undergoing allergen bronchoprovocation. Due to its high potency and ability to simultaneously suppress the activity of all 3 beta common cytokines, CSL311 may provide a new strategy for the treatment of chronic inflammatory diseases where the human betac receptor is central to pathogenesis. The coordinates for the betac/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU).
PDB ID: 5DWUDownload
MMDB ID: 135192
PDB Deposition Date: 2015/9/23
Updated in MMDB: 2015/12
Experimental Method:
x-ray diffraction
Resolution: 3.97  Å
Source Organism:
Similar Structures:
Biological Unit for 5DWU: tetrameric; determined by author and by software (PISA)
Molecular Components in 5DWU
Label Count Molecule
Proteins (4 molecules)
1
Cytokine Receptor Common Subunit Beta(Gene symbol: CSF2RB)
Molecule annotation
1
Cytokine Receptor Common Subunit Beta(Gene symbol: CSF2RB)
Molecule annotation
1
FAB - Heavy Chain
Molecule annotation
1
FAB - Light Chain
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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