5MGH
Crystal structure of pathogenic mutants of human mitochodnrial PheRS
Summary for 5MGH
| Entry DOI | 10.2210/pdb5mgh/pdb |
| Descriptor | Phenylalanine--tRNA ligase, mitochondrial, PHENYLALANINE (3 entities in total) |
| Functional Keywords | crystal structure of pathogenic human mitochondrial phers, molecular dynamic, kinetik study, aminoacylation, ligase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 47611.00 |
| Authors | Kartvelishvili, E.,Tworowski, D.,Vernon, H.,Chrzanowska-Lightowlers, Z.,Moor, N.,Wang, J.,Wong, L.-J.,Safro, M. (deposition date: 2016-11-21, release date: 2017-05-03, Last modification date: 2024-05-08) |
| Primary citation | Kartvelishvili, E.,Tworowski, D.,Vernon, H.,Moor, N.,Wang, J.,Wong, L.J.,Chrzanowska-Lightowlers, Z.,Safro, M. Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2. Protein Sci., 26:1505-1516, 2017 Cited by PubMed Abstract: Mutations in the mitochondrial aminoacyl-tRNA synthetases (mtaaRSs) can cause profound clinical presentations, and have manifested as diseases with very selective tissue specificity. To date most of the mtaaRS mutations could be phenotypically recognized, such that clinicians could identify the affected mtaaRS from the symptoms alone. Among the recently reported pathogenic variants are point mutations in FARS2 gene, encoding the human mitochondrial PheRS. Patient symptoms range from spastic paraplegia to fatal infantile Alpers encephalopathy. How clinical manifestations of these mutations relate to the changes in three-dimensional structures and kinetic characteristics remains unclear, although impaired aminoacylation has been proposed as possible etiology of diseases. Here, we report four crystal structures of HsmtPheRS mutants, and extensive MD simulations for wild-type and nine mutants to reveal the structural changes on dynamic trajectories of HsmtPheRS. Using steady-state kinetic measurements of phenylalanine activation and tRNA aminoacylation, we gained insight into the structural and kinetic effects of mitochondrial disease-related mutations in FARS2 gene. PubMed: 28419689DOI: 10.1002/pro.3176 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.87 Å) |
Structure validation
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