| Autor: |
Danfeng Shi, Xiaohong Zhu, Honghui Zhang, Junfang Yan, Chen Bai |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
iScience, Vol 27, Iss 9, Pp 110605- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2589-0042 |
| DOI: |
10.1016/j.isci.2024.110605 |
| Popis: |
Summary: ATP-citrate lyase (ACLY) is a critical metabolic enzyme and promising target for drug development. The structure determinations of ACLY have revealed its homotetramer states with various subunit symmetries, but catalytic mechanism of ACLY tetramer and the importance of subunit symmetry have not been clarified. Here, we constructed the free energy landscape of ACLY tetramer with arbitrary subunit symmetries and investigated energetic and conformational coupling of subunits during citryl-CoA synthesis process. The optimal conformational pathway indicates that ACLY tetramer encounters three critical conformational barriers and undergoes a loss of rigid-D2 symmetry to gain an energetic advantage. Energetic coupling of conformational changes and biochemical reactions suggests that these biological events are not independent but rather coupled with each other, showing a comparable energy barrier to the experimental data for the rate-limiting step. These findings could contribute to further research on catalytic mechanism, functional modulation, and inhibitor design of ACLY. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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