Acetyl-CoA carboxylases (ACCs) have been highlighted as therapeutic targets for obesity and diabetes, as they play crucial roles in fatty acid metabolism. ACC activity is regulated through the short-term mechanism of inactivation by reversible phosphorylation. Here, we report the crystal structures of the biotin carboxylase (BC) domain of human ACC2 phosphorylated by AMP-activated protein kinase (AMPK). The phosphorylated Ser222 binds to the putative dimer interface of BC, disrupting polymerization and providing the molecular mechanism of inactivation by AMPK. We also determined the structure of the human BC domain in complex with soraphen A, a macrocyclic polyketide natural product. This structure shows that the compound binds to the binding site of phosphorylated Ser222, implying that its inhibition mechanism is the same as that of phosphorylation by AMPK.
|Number of pages||6|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 2010 Jan 1|
Bibliographical noteFunding Information:
We thank the staffs at beamline 4A, Pohang Light Source (PLS), for their assistance. This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD). (KRF-2007-313- C00621 ) and by a Grant (Code # 20070501034003) from BioGreen 21 Program, Rural Development Administration, South Korea. And this work was supported by the Korea Research Foundation grants funded by the Korean Government (KRF-2008-313-C00745and KRF-2006-005- J04502 to H.S.C).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology