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Structural snapshots for the conformation-dependent catalysis by human medium-chain acyl-coenzyme A synthetase ACSM2A
- Source :
- Journal of molecular biology. 388(5)
- Publication Year :
- 2009
-
Abstract
- Acyl-CoA synthetases belong to the superfamily of adenylate-forming enzymes, and catalyze the two-step activation of fatty acids or carboxylate-containing xenobiotics. The carboxylate substrate first reacts with ATP to form an acyl-adenylate intermediate, which then reacts with CoA to produce an acyl-CoA ester. Here, we report the first crystal structure of a medium-chain acyl-CoA synthetase ACSM2A, in a series of substrate/product/cofactor complexes central to the catalytic mechanism. We observed a substantial rearrangement between the N- and C-terminal domains, driven purely by the identity of the bound ligand in the active site. Our structures allowed us to identify the presence or absence of the ATP pyrophosphates as the conformational switch, and elucidated new mechanistic details, including the role of invariant Lys557 and a divalent magnesium ion in coordinating the ATP pyrophosphates, as well as the involvement of a Gly-rich P-loop and the conserved Arg472-Glu365 salt bridge in the domain rearrangement.
- Subjects :
- Models, Molecular
Stereochemistry
Protein Conformation
Coenzyme A
Molecular Sequence Data
Molecular Conformation
chemistry
Crystallography, X-Ray
Cofactor
Catalysis
Substrate Specificity
chemistry.chemical_compound
Protein structure
Adenosine Triphosphate
Structural Biology
Coenzyme A Ligases
Humans
genetics
Amino Acid Sequence
Molecular Biology
Magnesium ion
Binding Sites
biology
Fatty Acids
Active site
Adenosine Monophosphate
Isoenzymes
biology.protein
Salt bridge
Adenosine triphosphate
metabolism
Sequence Alignment
Subjects
Details
- Language :
- English
- ISSN :
- 10898638 and 00222836
- Volume :
- 388
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Journal of molecular biology
- Accession number :
- edsair.doi.dedup.....6fb8b34fa074c1492779b06cc293c88e