5dwu
Beta common receptor in complex with a Fab
Structural highlights
DiseaseIL3RB_HUMAN Defects in CSF2RB are the cause of pulmonary surfactant metabolism dysfunction type 5 (SMDP5) [MIM:614370. SMDP5 is a rare lung disorder due to impaired surfactant homeostasis. It is characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff method and is derived from surfactant phospholipids and protein components. Excessive lipoproteins accumulation in the alveoli results in severe respiratory distress.[1] FunctionIL3RB_HUMAN High affinity receptor for interleukin-3, interleukin-5 and granulocyte-macrophage colony-stimulating factor. Publication Abstract from PubMedThe beta common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of hematopoietic 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 three 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 three 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). CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common beta chain of the IL-3, GM-CSF and IL-5 receptors.,Panousis C, Dhagat U, Edwards KM, Rayzman V, Hardy MP, Braley H, Gauvreau GM, Hercus TR, Smith S, Sehmi R, McMillan L, Dottore M, McClure BJ, Fabri LJ, Vairo G, Lopez AF, Parker MW, Nash AD, Wilson NJ, Wilson MJ, Owczarek CM MAbs. 2015 Dec 14:0. PMID:26651396[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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