Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in human guanylate-binding protein 2
Abstract Guanylate-binding proteins (GBPs) are interferon-inducible GTPases that confer protective immunity against a variety of intracellular pathogens. GBP2 is one of the two highly inducible GBPs, yet the precise mechanisms underlying the activation and regulation of GBP2, in particular the nucle...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07727-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850190943784796160 |
|---|---|
| author | Sayantan Roy Bing Wang Krittika Roy Yuan Tian Madhurima Bhattacharya Sarah Williams Qian Yin |
| author_facet | Sayantan Roy Bing Wang Krittika Roy Yuan Tian Madhurima Bhattacharya Sarah Williams Qian Yin |
| author_sort | Sayantan Roy |
| collection | DOAJ |
| description | Abstract Guanylate-binding proteins (GBPs) are interferon-inducible GTPases that confer protective immunity against a variety of intracellular pathogens. GBP2 is one of the two highly inducible GBPs, yet the precise mechanisms underlying the activation and regulation of GBP2, in particular the nucleotide-induced conformational changes in GBP2, remain poorly understood. In this study, we elucidate the structural plasticity of GBP2 upon nucleotide binding through crystallographic analysis. By determining the crystal structures of GBP2 G domain (GBP2GD) in complex with GDP and nucleotide-free full-length GBP2 with K51A mutation (GBP2K51A), we unveil distinct conformational states adopted by the nucleotide-binding pocket and distal regions of the protein. Comparison between the nucleotide-free full-length GBP2K51A structure with homologous structures reveals notable movement in the C-terminal helical region, along with conformational changes in the G domain. Through comparative analysis, we identify subtle but critical differences in the nucleotide-bound states of GBP2, providing insights into the molecular basis of its dimer-monomer transition and enzymatic activity. These findings pave the way for future investigations aimed at elucidating the precise molecular mechanisms underlying GBP2’s role in the immune response and open avenues for exploring how the unique functions of GBPs could be leveraged to combat pathogen invasion. |
| format | Article |
| id | doaj-art-4963bcdf62b343ab90612c97c94ffcc2 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-4963bcdf62b343ab90612c97c94ffcc22025-08-20T02:15:06ZengNature PortfolioCommunications Biology2399-36422025-02-018111210.1038/s42003-025-07727-3Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in human guanylate-binding protein 2Sayantan Roy0Bing Wang1Krittika Roy2Yuan Tian3Madhurima Bhattacharya4Sarah Williams5Qian Yin6Department of Biological Science, Florida State UniversityDepartment of Biological Science, Florida State UniversityInstitute of Molecular Biophysics, Florida State UniversityDepartment of Biological Science, Florida State UniversityInstitute of Molecular Biophysics, Florida State UniversityInstitute of Molecular Biophysics, Florida State UniversityDepartment of Biological Science, Florida State UniversityAbstract Guanylate-binding proteins (GBPs) are interferon-inducible GTPases that confer protective immunity against a variety of intracellular pathogens. GBP2 is one of the two highly inducible GBPs, yet the precise mechanisms underlying the activation and regulation of GBP2, in particular the nucleotide-induced conformational changes in GBP2, remain poorly understood. In this study, we elucidate the structural plasticity of GBP2 upon nucleotide binding through crystallographic analysis. By determining the crystal structures of GBP2 G domain (GBP2GD) in complex with GDP and nucleotide-free full-length GBP2 with K51A mutation (GBP2K51A), we unveil distinct conformational states adopted by the nucleotide-binding pocket and distal regions of the protein. Comparison between the nucleotide-free full-length GBP2K51A structure with homologous structures reveals notable movement in the C-terminal helical region, along with conformational changes in the G domain. Through comparative analysis, we identify subtle but critical differences in the nucleotide-bound states of GBP2, providing insights into the molecular basis of its dimer-monomer transition and enzymatic activity. These findings pave the way for future investigations aimed at elucidating the precise molecular mechanisms underlying GBP2’s role in the immune response and open avenues for exploring how the unique functions of GBPs could be leveraged to combat pathogen invasion.https://doi.org/10.1038/s42003-025-07727-3 |
| spellingShingle | Sayantan Roy Bing Wang Krittika Roy Yuan Tian Madhurima Bhattacharya Sarah Williams Qian Yin Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in human guanylate-binding protein 2 Communications Biology |
| title | Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in human guanylate-binding protein 2 |
| title_full | Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in human guanylate-binding protein 2 |
| title_fullStr | Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in human guanylate-binding protein 2 |
| title_full_unstemmed | Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in human guanylate-binding protein 2 |
| title_short | Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in human guanylate-binding protein 2 |
| title_sort | crystal structures reveal nucleotide induced conformational changes in g motifs and distal regions in human guanylate binding protein 2 |
| url | https://doi.org/10.1038/s42003-025-07727-3 |
| work_keys_str_mv | AT sayantanroy crystalstructuresrevealnucleotideinducedconformationalchangesingmotifsanddistalregionsinhumanguanylatebindingprotein2 AT bingwang crystalstructuresrevealnucleotideinducedconformationalchangesingmotifsanddistalregionsinhumanguanylatebindingprotein2 AT krittikaroy crystalstructuresrevealnucleotideinducedconformationalchangesingmotifsanddistalregionsinhumanguanylatebindingprotein2 AT yuantian crystalstructuresrevealnucleotideinducedconformationalchangesingmotifsanddistalregionsinhumanguanylatebindingprotein2 AT madhurimabhattacharya crystalstructuresrevealnucleotideinducedconformationalchangesingmotifsanddistalregionsinhumanguanylatebindingprotein2 AT sarahwilliams crystalstructuresrevealnucleotideinducedconformationalchangesingmotifsanddistalregionsinhumanguanylatebindingprotein2 AT qianyin crystalstructuresrevealnucleotideinducedconformationalchangesingmotifsanddistalregionsinhumanguanylatebindingprotein2 |