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Crystal structure of CD27 in complex with a neutralizing noncompeting antibody

Crystal structure of CD27 in complex with a neutralizing noncompeting antibody CD27 is a T‐cell and B‐cell co‐stimulatory glycoprotein of the tumor necrosis factor (TNF) receptor superfamily that is dependent on the availability of the TNF‐like ligand CD70. Therapeutic approaches to treating autoimmune diseases and cancers with antagonistic and agonistic anti‐CD27 monoclonal antibodies (mAbs), respectively, have recently been developed. Mouse anti‐human CD27 mAb 2177 shows potency in neutralizing CD70‐induced signaling; however, it does not block the binding of soluble CD70. To provide insight into the mechanism of action of the mAb, the crystal structure of the CD27 extracellular domain in complex with the Fab fragment of mAb 2177 was determined at 1.8 Å resolution. CD27 exhibits the assembly of cysteine‐rich domains characteristic of the TNF receptor superfamily. The structure reveals a unique binding site of mAb 2177 at the edge of the receptor molecule, which allows the mAb to sterically block the cell‐bound form of CD70 from reaching CD27 while leaving the ligand epitope clear. This mode of action suggests a potential dual use of mAb 2177 either as an antagonist or as an agonist. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Crystallographica Section F Wiley

Crystal structure of CD27 in complex with a neutralizing noncompeting antibody

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References (46)

Publisher
Wiley
Copyright
Copyright © 2017 Wiley Subscription Services
ISSN
2053-230X
eISSN
2053-230X
DOI
10.1107/S2053230X17005957
pmid
28471362
Publisher site
See Article on Publisher Site

Abstract

CD27 is a T‐cell and B‐cell co‐stimulatory glycoprotein of the tumor necrosis factor (TNF) receptor superfamily that is dependent on the availability of the TNF‐like ligand CD70. Therapeutic approaches to treating autoimmune diseases and cancers with antagonistic and agonistic anti‐CD27 monoclonal antibodies (mAbs), respectively, have recently been developed. Mouse anti‐human CD27 mAb 2177 shows potency in neutralizing CD70‐induced signaling; however, it does not block the binding of soluble CD70. To provide insight into the mechanism of action of the mAb, the crystal structure of the CD27 extracellular domain in complex with the Fab fragment of mAb 2177 was determined at 1.8 Å resolution. CD27 exhibits the assembly of cysteine‐rich domains characteristic of the TNF receptor superfamily. The structure reveals a unique binding site of mAb 2177 at the edge of the receptor molecule, which allows the mAb to sterically block the cell‐bound form of CD70 from reaching CD27 while leaving the ligand epitope clear. This mode of action suggests a potential dual use of mAb 2177 either as an antagonist or as an agonist.

Journal

Acta Crystallographica Section FWiley

Published: Jan 1, 2017

Keywords: ; ; ; ; ;

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