Tertiary and quaternary structure remodeling by occupancy of the substrate binding pocket in a large glutamate dehydrogenase
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| Format: | Artículo Open Access |
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2026
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| author | Melisa Lázaro Nicolás Chamorro Jorge P. López‐Alonso Diego Charro Rodolfo M. Rasia Gonzalo Jiménez‐Osés Mikel Valle María‐Natalia Lisa |
| author_facet | Melisa Lázaro Nicolás Chamorro Jorge P. López‐Alonso Diego Charro Rodolfo M. Rasia Gonzalo Jiménez‐Osés Mikel Valle María‐Natalia Lisa Melisa Lázaro Nicolás Chamorro Jorge P. López‐Alonso Diego Charro Rodolfo M. Rasia Gonzalo Jiménez‐Osés Mikel Valle María‐Natalia Lisa |
| collection | Wiley Open Access |
| contents | Tertiary and quaternary structure remodeling by occupancy of the substrate binding pocket in a large glutamate dehydrogenase Melisa Lázaro Nicolás Chamorro Jorge P. López‐Alonso Diego Charro Rodolfo M. Rasia Gonzalo Jiménez‐Osés Mikel Valle María‐Natalia Lisa Protein Science Abstract Glutamate dehydrogenases (GDHs) catalyze the oxidative deamination of L‐glutamate to 2‐oxoglutarate using NAD(P) + as a cofactor. The large type of GDHs (L‐GDHs) displays a dynamic homotetrameric architecture that alternates between open and closed states. However, the catalytic mechanism and the functional relevance of the large conformational changes in L‐GDHs remain poorly understood. Here, we use cryo‐EM to investigate the structure and the conformational landscape of the mycobacterial L‐GDH composed of 180 kDa subunits (mL‐GDH 180 ) when incubated with L‐glutamate and NAD + . Classification of the heterogeneous population of tetramers reveals opening‐closing motions and sorting of individual subunits resolves the occupancy of the cofactor and substrate binding pockets. Cryo‐EM maps show that ligand binding to the glutamate binding pocket is accompanied by structural changes in a region approximately two nanometers away from the active site, leading to the formation of a previously undetected interaction between the catalytic domains of neighboring subunits in mL‐GDH 180 closed tetrameric states. Our findings indicate that the occupancy of the substrate binding site of mL‐GDH 180 is linked to a remodeling of both the tertiary and quaternary structure of the enzyme. 10.1002/pro.70544 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/pro.70544 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_pro_70544 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2026 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Tertiary and quaternary structure remodeling by occupancy of the substrate binding pocket in a large glutamate dehydrogenase Melisa Lázaro Nicolás Chamorro Jorge P. López‐Alonso Diego Charro Rodolfo M. Rasia Gonzalo Jiménez‐Osés Mikel Valle María‐Natalia Lisa Protein Science Tertiary and quaternary structure remodeling by occupancy of the substrate binding pocket in a large glutamate dehydrogenase Melisa Lázaro Nicolás Chamorro Jorge P. López‐Alonso Diego Charro Rodolfo M. Rasia Gonzalo Jiménez‐Osés Mikel Valle María‐Natalia Lisa Protein Science Abstract Glutamate dehydrogenases (GDHs) catalyze the oxidative deamination of L‐glutamate to 2‐oxoglutarate using NAD(P) + as a cofactor. The large type of GDHs (L‐GDHs) displays a dynamic homotetrameric architecture that alternates between open and closed states. However, the catalytic mechanism and the functional relevance of the large conformational changes in L‐GDHs remain poorly understood. Here, we use cryo‐EM to investigate the structure and the conformational landscape of the mycobacterial L‐GDH composed of 180 kDa subunits (mL‐GDH 180 ) when incubated with L‐glutamate and NAD + . Classification of the heterogeneous population of tetramers reveals opening‐closing motions and sorting of individual subunits resolves the occupancy of the cofactor and substrate binding pockets. Cryo‐EM maps show that ligand binding to the glutamate binding pocket is accompanied by structural changes in a region approximately two nanometers away from the active site, leading to the formation of a previously undetected interaction between the catalytic domains of neighboring subunits in mL‐GDH 180 closed tetrameric states. Our findings indicate that the occupancy of the substrate binding site of mL‐GDH 180 is linked to a remodeling of both the tertiary and quaternary structure of the enzyme. 10.1002/pro.70544 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Tertiary and quaternary structure remodeling by occupancy of the substrate binding pocket in a large glutamate dehydrogenase |
| topic | Protein Science |
| url | https://onlinelibrary.wiley.com/doi/10.1002/pro.70544 |