Experimental and Computational Insights into the Structural Dynamics of the Fc Fragment of IgG1 Subtype from Biosimilar VEGF‐Trap
The constant fragment (Fc) of the immunoglobulin G1 (IgG1) subtype is increasingly recognized as a crucial scaffold in the development of advanced therapeutics due to its enhanced specificity, efficacy, and extended half‐life. A prime example is VEGF‐Trap (Aflibercept), a recombinant fusion protein...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley-VCH
2025-08-01
|
| Series: | Small Structures |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/sstr.202400680 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850036388677812224 |
|---|---|
| author | Ebru Destan Engin Turkut Alper Aldeniz Jungmin Kang Takehiko Tosha Makina Yabashi Baris Yilmaz Ahmet Can Timucin Hiroaki Matsuura Yoshiaki Kawano Irfan Cinkaya Hasan DeMirci |
| author_facet | Ebru Destan Engin Turkut Alper Aldeniz Jungmin Kang Takehiko Tosha Makina Yabashi Baris Yilmaz Ahmet Can Timucin Hiroaki Matsuura Yoshiaki Kawano Irfan Cinkaya Hasan DeMirci |
| author_sort | Ebru Destan |
| collection | DOAJ |
| description | The constant fragment (Fc) of the immunoglobulin G1 (IgG1) subtype is increasingly recognized as a crucial scaffold in the development of advanced therapeutics due to its enhanced specificity, efficacy, and extended half‐life. A prime example is VEGF‐Trap (Aflibercept), a recombinant fusion protein that merges the Fc region of the IgG1 subtype with the binding domains of vascular endothelial growth factor receptors (VEGFR)‐1 and VEGFR‐2. The Fc region's role in N‐glycosylation is particularly important, as it significantly influences protein stability. Herein, the first near‐physiological temperature structures of the N‐glycan‐bound Fc fragment of IgG1 subtype from a biosimilar VEGF‐Trap are presented, determined using the SPring‐8 Angstrom Compact free electron LAser (SACLA) and the Turkish Light Source (Turkish DeLight). Comparative analysis with cryogenic structures, including existing data, reveals alternate conformations within the glycan‐binding pocket. Furthermore, molecular dynamics simulations indicate the presence of a high degree of structural plasticity, explaining how the protein adapts its structure through conformational changes. The observed structural fluctuations/conformational changes demonstrate the effect of N‐glycans on protein stability. These findings offer new insights into the molecular basis of Fc‐mediated functions and provide valuable information for the design of next‐generation therapeutics. |
| format | Article |
| id | doaj-art-a67d82ab3a7b4a9dba9adac820af8034 |
| institution | DOAJ |
| issn | 2688-4062 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley-VCH |
| record_format | Article |
| series | Small Structures |
| spelling | doaj-art-a67d82ab3a7b4a9dba9adac820af80342025-08-20T02:57:08ZengWiley-VCHSmall Structures2688-40622025-08-0168n/an/a10.1002/sstr.202400680Experimental and Computational Insights into the Structural Dynamics of the Fc Fragment of IgG1 Subtype from Biosimilar VEGF‐TrapEbru Destan0Engin Turkut1Alper Aldeniz2Jungmin Kang3Takehiko Tosha4Makina Yabashi5Baris Yilmaz6Ahmet Can Timucin7Hiroaki Matsuura8Yoshiaki Kawano9Irfan Cinkaya10Hasan DeMirci11Department of Molecular Biology and Genetics Koc University 34450 Istanbul TürkiyeBiotechnology DEVA Holding AS 59510 Tekirdag TürkiyeBiotechnology DEVA Holding AS 59510 Tekirdag TürkiyeRIKEN SPring‐8 Center 1‐1‐1 Kouto Sayo‐cho, Sayo‐gun Hyogo 679‐5148 JapanRIKEN SPring‐8 Center 1‐1‐1 Kouto Sayo‐cho, Sayo‐gun Hyogo 679‐5148 JapanRIKEN SPring‐8 Center 1‐1‐1 Kouto Sayo‐cho, Sayo‐gun Hyogo 679‐5148 JapanBiotechnology DEVA Holding AS 59510 Tekirdag TürkiyeDepartment of Molecular Biology and Genetics Acibadem University 34752 Istanbul TürkiyeRIKEN SPring‐8 Center 1‐1‐1 Kouto Sayo‐cho, Sayo‐gun Hyogo 679‐5148 JapanRIKEN SPring‐8 Center 1‐1‐1 Kouto Sayo‐cho, Sayo‐gun Hyogo 679‐5148 JapanBiotechnology DEVA Holding AS 59510 Tekirdag TürkiyeDepartment of Molecular Biology and Genetics Koc University 34450 Istanbul TürkiyeThe constant fragment (Fc) of the immunoglobulin G1 (IgG1) subtype is increasingly recognized as a crucial scaffold in the development of advanced therapeutics due to its enhanced specificity, efficacy, and extended half‐life. A prime example is VEGF‐Trap (Aflibercept), a recombinant fusion protein that merges the Fc region of the IgG1 subtype with the binding domains of vascular endothelial growth factor receptors (VEGFR)‐1 and VEGFR‐2. The Fc region's role in N‐glycosylation is particularly important, as it significantly influences protein stability. Herein, the first near‐physiological temperature structures of the N‐glycan‐bound Fc fragment of IgG1 subtype from a biosimilar VEGF‐Trap are presented, determined using the SPring‐8 Angstrom Compact free electron LAser (SACLA) and the Turkish Light Source (Turkish DeLight). Comparative analysis with cryogenic structures, including existing data, reveals alternate conformations within the glycan‐binding pocket. Furthermore, molecular dynamics simulations indicate the presence of a high degree of structural plasticity, explaining how the protein adapts its structure through conformational changes. The observed structural fluctuations/conformational changes demonstrate the effect of N‐glycans on protein stability. These findings offer new insights into the molecular basis of Fc‐mediated functions and provide valuable information for the design of next‐generation therapeutics.https://doi.org/10.1002/sstr.202400680immunoglobulinN‐glycosylationprotein dynamicsstructural biology |
| spellingShingle | Ebru Destan Engin Turkut Alper Aldeniz Jungmin Kang Takehiko Tosha Makina Yabashi Baris Yilmaz Ahmet Can Timucin Hiroaki Matsuura Yoshiaki Kawano Irfan Cinkaya Hasan DeMirci Experimental and Computational Insights into the Structural Dynamics of the Fc Fragment of IgG1 Subtype from Biosimilar VEGF‐Trap Small Structures immunoglobulin N‐glycosylation protein dynamics structural biology |
| title | Experimental and Computational Insights into the Structural Dynamics of the Fc Fragment of IgG1 Subtype from Biosimilar VEGF‐Trap |
| title_full | Experimental and Computational Insights into the Structural Dynamics of the Fc Fragment of IgG1 Subtype from Biosimilar VEGF‐Trap |
| title_fullStr | Experimental and Computational Insights into the Structural Dynamics of the Fc Fragment of IgG1 Subtype from Biosimilar VEGF‐Trap |
| title_full_unstemmed | Experimental and Computational Insights into the Structural Dynamics of the Fc Fragment of IgG1 Subtype from Biosimilar VEGF‐Trap |
| title_short | Experimental and Computational Insights into the Structural Dynamics of the Fc Fragment of IgG1 Subtype from Biosimilar VEGF‐Trap |
| title_sort | experimental and computational insights into the structural dynamics of the fc fragment of igg1 subtype from biosimilar vegf trap |
| topic | immunoglobulin N‐glycosylation protein dynamics structural biology |
| url | https://doi.org/10.1002/sstr.202400680 |
| work_keys_str_mv | AT ebrudestan experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT enginturkut experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT alperaldeniz experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT jungminkang experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT takehikotosha experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT makinayabashi experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT barisyilmaz experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT ahmetcantimucin experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT hiroakimatsuura experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT yoshiakikawano experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT irfancinkaya experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap AT hasandemirci experimentalandcomputationalinsightsintothestructuraldynamicsofthefcfragmentofigg1subtypefrombiosimilarvegftrap |