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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 a...

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Autores principales: Teplyakov, Alexey, Obmolova, Galina, Malia, Thomas J., Gilliland, Gary L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417320/
https://www.ncbi.nlm.nih.gov/pubmed/28471362
http://dx.doi.org/10.1107/S2053230X17005957
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author Teplyakov, Alexey
Obmolova, Galina
Malia, Thomas J.
Gilliland, Gary L.
author_facet Teplyakov, Alexey
Obmolova, Galina
Malia, Thomas J.
Gilliland, Gary L.
author_sort Teplyakov, Alexey
collection PubMed
description 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.
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spelling pubmed-54173202017-05-16 Crystal structure of CD27 in complex with a neutralizing noncompeting antibody Teplyakov, Alexey Obmolova, Galina Malia, Thomas J. Gilliland, Gary L. Acta Crystallogr F Struct Biol Commun Research Communications 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. International Union of Crystallography 2017-04-26 /pmc/articles/PMC5417320/ /pubmed/28471362 http://dx.doi.org/10.1107/S2053230X17005957 Text en © Teplyakov et al. 2017 http://creativecommons.org/licenses/by/2.0/uk/ This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.http://creativecommons.org/licenses/by/2.0/uk/
spellingShingle Research Communications
Teplyakov, Alexey
Obmolova, Galina
Malia, Thomas J.
Gilliland, Gary L.
Crystal structure of CD27 in complex with a neutralizing noncompeting antibody
title Crystal structure of CD27 in complex with a neutralizing noncompeting antibody
title_full Crystal structure of CD27 in complex with a neutralizing noncompeting antibody
title_fullStr Crystal structure of CD27 in complex with a neutralizing noncompeting antibody
title_full_unstemmed Crystal structure of CD27 in complex with a neutralizing noncompeting antibody
title_short Crystal structure of CD27 in complex with a neutralizing noncompeting antibody
title_sort crystal structure of cd27 in complex with a neutralizing noncompeting antibody
topic Research Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417320/
https://www.ncbi.nlm.nih.gov/pubmed/28471362
http://dx.doi.org/10.1107/S2053230X17005957
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