Induced conformational change in human IL‐4 upon binding of a signal‐neutralizing DARPin. Issue 6 (8th May 2015)

• Record Type: Journal Article
• Authors: Obmolova, Galina; Teplyakov, Alexey; Malia, Thomas J.; Keough, Edward; Luo, Jinquan; Sweet, Raymond; Jacobs, Steven A.; Yi, Fang; Hippensteel, Randi; O'Neil, Karyn T.; Gilliland, Gary L.
• Is Part Of: Proteins. Volume 83:Issue 6(2015)
• Page Start: 1191
• Page End: 1197
• Publication Date: 2015-05-08
• Subjects: Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.24815
• Languages: English
• ISSNs: 0887-3585

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>The crystal structure of DARPin 44C12V5 that neutralizes IL‐4 signaling has been determined alone and bound to human IL‐4. A significant conformational change occurs in the IL‐4 upon DARPin binding. The DARPin binds to the face of IL‐4 formed by the A and C α‐helices. The structure of the DARPin remains virtually unchanged. The conformational changes in IL‐4 include a reorientation of the C‐helix Trp91 side chain and repositioning of CD‐loop residue Leu96. Both side chains move by >9 Å, becoming buried in the central hydrophobic region of the IL‐4:DARPin interface. This hydrophobic region is surrounded by a ring of hydrophilic interactions comprised of hydrogen bonds and salt bridges and represents a classical "hotspot." The structures also reveal how the DARPin neutralizes IL‐4 signaling. Comparing the IL‐4:DARPin complex structure with the structures of IL‐4 bound to its receptors (Hage <italic>et al</italic>., Cell 1999; <bold>97</bold>, 271‐281; La Porte <italic>et al</italic>., Cell 2008, 132, 259‐272), it is found that the DARPin binds to the same IL‐4 face that interacts with the junction of the D1 and D2 domains of the IL‐4Rα receptors. Signaling is blocked since IL‐4 cannot bind to this receptor, which it must do first before initiating a productive receptor complex with either the IL‐13α1 or the <italic>γ</italic><sub>c</sub> receptor. Proteins 2015; 83:1191–1197. © 2015 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.</p> </abstract>