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| Title | The cryo-EM structure of trypanosome 3-methylcrotonyl-CoA carboxylase provides mechanistic and dynamic insights into its enzymatic function. |
|---|---|
| Journal, issue, pages | Structure, Year 2024 |
| Publish date | Apr 5, 2024 |
 Authors | Adrián Plaza-Pegueroles / Inna Aphasizheva / Ruslan Aphasizhev / Carlos Fernández-Tornero / Federico M Ruiz /   |
| PubMed Abstract | 3-Methylcrotonyl-CoA carboxylase (MCC) catalyzes the two-step, biotin-dependent production of 3-methylglutaconyl-CoA, an essential intermediate in leucine catabolism. Given the critical metabolic ...3-Methylcrotonyl-CoA carboxylase (MCC) catalyzes the two-step, biotin-dependent production of 3-methylglutaconyl-CoA, an essential intermediate in leucine catabolism. Given the critical metabolic role of MCC, deficiencies in this enzyme lead to organic aciduria, while its overexpression is linked to tumor development. MCC is a dodecameric enzyme composed of six copies of each α- and β-subunit. We present the cryo-EM structure of the endogenous MCC holoenzyme from Trypanosoma brucei in a non-filamentous state at 2.4 Å resolution. Biotin is covalently bound to the biotin carboxyl carrier protein domain of α-subunits and positioned in a non-canonical pocket near the active site of neighboring β-subunit dimers. Moreover, flexibility of key residues at α-subunit interfaces and loops enables pivoting of α-subunit trimers to partly reduce the distance between α- and β-subunit active sites, required for MCC catalysis. Our results provide a structural framework to understand the enzymatic mechanism of eukaryotic MCCs and to assist drug discovery against trypanosome infections. |
 External links | Structure / PubMed:38593794 |
| Methods | EM (single particle) |
| Resolution | 2.37 Å |
| Structure data | EMDB-19492, PDB-8rth: |
| Chemicals |  ChemComp-BTI: |
| Source |
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 Keywords |  TRANSFERASE / carboxylase / trypanosoma brucei / BIOSYNTHETIC PROTEIN |
