Fab Fragment of VHH-Based Antibody Netakimab: Crystal Structure and Modeling Interaction with Cytokine IL-17A

Interleukin 17A (IL-17A) is a proinflammatory cytokine produced by Th17 cells. Antibody BCD-085 (netakimab) against human IL-17A is one of the new inhibitors of this cytokine. In netakimab, the VH domain is replaced by the VHH domain of Lama gla...

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Main Authors:	Olga Kostareva, Ilya Kolyadenko, Andrey Ulitin, Victoria Ekimova, Stanislav Evdokimov, Maria Garber, Svetlana Tishchenko, Azat Gabdulkhakov
Format:	Article
Language:	English
Published:	MDPI AG 2019-03-01
Series:	Crystals
Subjects:	V<sub>H</sub>H domain Fab fragment netakimab crystal structure complementarity determining regions interleukin 17A
Online Access:	https://www.mdpi.com/2073-4352/9/3/177

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spelling	doaj-fc5a37a0177544e2a0b92bff5b4e19552020-11-24T20:43:27ZengMDPI AGCrystals2073-43522019-03-019317710.3390/cryst9030177cryst9030177Fab Fragment of V<sub>H</sub>H-Based Antibody Netakimab: Crystal Structure and Modeling Interaction with Cytokine IL-17AOlga Kostareva0Ilya Kolyadenko1Andrey Ulitin2Victoria Ekimova3Stanislav Evdokimov4Maria Garber5Svetlana Tishchenko6Azat Gabdulkhakov7Institute of Protein Research RAS, Institutskaya 4, Pushchino, Moscow 142290, RussiaInstitute of Protein Research RAS, Institutskaya 4, Pushchino, Moscow 142290, RussiaCJSC Biocad, ul.Svyazi., 34-A, p. Strelna, Saint-Petersburg, Leningrad 198515, RussiaCJSC Biocad, ul.Svyazi., 34-A, p. Strelna, Saint-Petersburg, Leningrad 198515, RussiaCJSC Biocad, ul.Svyazi., 34-A, p. Strelna, Saint-Petersburg, Leningrad 198515, RussiaInstitute of Protein Research RAS, Institutskaya 4, Pushchino, Moscow 142290, RussiaInstitute of Protein Research RAS, Institutskaya 4, Pushchino, Moscow 142290, RussiaInstitute of Protein Research RAS, Institutskaya 4, Pushchino, Moscow 142290, RussiaInterleukin 17A (IL-17A) is a proinflammatory cytokine produced by Th17 cells. Antibody BCD-085 (netakimab) against human IL-17A is one of the new inhibitors of this cytokine. In netakimab, the V<sub>H</sub> domain is replaced by the V<sub>H</sub>H domain of <i>Lama glama</i> possessing a long complementarity determining region (CDR-H3) in its heavy chain. Here we demonstrate the high affinity of IL-17A to the Fab fragment of netakimab and to its integral part, the V<sub>H</sub>H domain. We have determined the crystal structure of the Fab fragment of netakimab at 1.9 Å resolution. High variability in the orientation of light and heavy chains of the Fab fragment of netakimab was shown, which is determined by the peculiarity of the structural organization of the CDR-H3. As the high conformational plasticity of the molecule hampers modeling the Fab fragment of netakimab complexed to IL-17A, we have carried out modeling the complex between the antigen and the integral part of the Fab fragment, the V<sub>H</sub>H domain. We explain the high netakimab Fab fragment affinity for IL-17A by a large number of protein–protein contacts due to additional interactions between CDR-H3 and the cytokine dimer.https://www.mdpi.com/2073-4352/9/3/177V<sub>H</sub>H domainFab fragmentnetakimabcrystal structurecomplementarity determining regionsinterleukin 17A
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Olga Kostareva Ilya Kolyadenko Andrey Ulitin Victoria Ekimova Stanislav Evdokimov Maria Garber Svetlana Tishchenko Azat Gabdulkhakov
spellingShingle	Olga Kostareva Ilya Kolyadenko Andrey Ulitin Victoria Ekimova Stanislav Evdokimov Maria Garber Svetlana Tishchenko Azat Gabdulkhakov Fab Fragment of V<sub>H</sub>H-Based Antibody Netakimab: Crystal Structure and Modeling Interaction with Cytokine IL-17A Crystals V<sub>H</sub>H domain Fab fragment netakimab crystal structure complementarity determining regions interleukin 17A
author_facet	Olga Kostareva Ilya Kolyadenko Andrey Ulitin Victoria Ekimova Stanislav Evdokimov Maria Garber Svetlana Tishchenko Azat Gabdulkhakov
author_sort	Olga Kostareva
title	Fab Fragment of V<sub>H</sub>H-Based Antibody Netakimab: Crystal Structure and Modeling Interaction with Cytokine IL-17A
title_short	Fab Fragment of V<sub>H</sub>H-Based Antibody Netakimab: Crystal Structure and Modeling Interaction with Cytokine IL-17A
title_full	Fab Fragment of V<sub>H</sub>H-Based Antibody Netakimab: Crystal Structure and Modeling Interaction with Cytokine IL-17A
title_fullStr	Fab Fragment of V<sub>H</sub>H-Based Antibody Netakimab: Crystal Structure and Modeling Interaction with Cytokine IL-17A
title_full_unstemmed	Fab Fragment of V<sub>H</sub>H-Based Antibody Netakimab: Crystal Structure and Modeling Interaction with Cytokine IL-17A
title_sort	fab fragment of v<sub>h</sub>h-based antibody netakimab: crystal structure and modeling interaction with cytokine il-17a
publisher	MDPI AG
series	Crystals
issn	2073-4352
publishDate	2019-03-01
description	Interleukin 17A (IL-17A) is a proinflammatory cytokine produced by Th17 cells. Antibody BCD-085 (netakimab) against human IL-17A is one of the new inhibitors of this cytokine. In netakimab, the V<sub>H</sub> domain is replaced by the V<sub>H</sub>H domain of <i>Lama glama</i> possessing a long complementarity determining region (CDR-H3) in its heavy chain. Here we demonstrate the high affinity of IL-17A to the Fab fragment of netakimab and to its integral part, the V<sub>H</sub>H domain. We have determined the crystal structure of the Fab fragment of netakimab at 1.9 Å resolution. High variability in the orientation of light and heavy chains of the Fab fragment of netakimab was shown, which is determined by the peculiarity of the structural organization of the CDR-H3. As the high conformational plasticity of the molecule hampers modeling the Fab fragment of netakimab complexed to IL-17A, we have carried out modeling the complex between the antigen and the integral part of the Fab fragment, the V<sub>H</sub>H domain. We explain the high netakimab Fab fragment affinity for IL-17A by a large number of protein–protein contacts due to additional interactions between CDR-H3 and the cytokine dimer.
topic	V<sub>H</sub>H domain Fab fragment netakimab crystal structure complementarity determining regions interleukin 17A
url	https://www.mdpi.com/2073-4352/9/3/177
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Fab Fragment of V<sub>H</sub>H-Based Antibody Netakimab: Crystal Structure and Modeling Interaction with Cytokine IL-17A

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