1W93

Crystal Structure of Biotin Carboxylase Domain of Acetyl-Coenzyme A Carboxylase from Saccharomyces cerevisiae

Summary for 1W93

• Entry DOI: 10.2210/pdb1w93/pdb
• Related: 1OD2 1OD4 1UYR 1UYS 1UYT 1UYV 1W2X
• Descriptor: ACETYL-COENZYME A CARBOXYLASE (2 entities in total)
• Functional Keywords: obesity, diabetes, fatty acid metabolism, structure-based drug design, allosteric inhibition, polyketide, ligase
• Biological source: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST)
• Cellular location: Cytoplasm: Q00955
• Total number of polymer chains: 1
• Total formula weight: 61523.17

Authors

Shen, Y.,Volrath, S.L.,Weatherly, S.C.,Elich, T.D.,Tong, L. (deposition date: 2004-10-05, release date: 2005-01-04, Last modification date: 2024-05-08)

Primary citation

Shen, Y.,Volrath, S.L.,Weatherly, S.C.,Elich, T.D.,Tong, L.
A Mechanism for the Potent Inhibition of Eukaryotic Acetyl-Coenzyme a Carboxylase by Soraphen A, a Macrocyclic Polyketide Natural Product
Mol.Cell, 16:881-, 2004

PubMed Abstract: Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism. Soraphen A, a macrocyclic polyketide natural product, is a nanomolar inhibitor against the biotin carboxylase (BC) domain of human, yeast, and other eukaryotic ACCs. Here we report the crystal structures of the yeast BC domain, alone and in complex with soraphen A. Soraphen has extensive interactions with an allosteric site, about 25 A from the active site. The specificity of soraphen is explained by large structural differences between the eukaryotic and prokaryotic BC in its binding site, confirmed by our studies on the effects of single-site mutations in this binding site. Unexpectedly, our structures suggest that soraphen may bind in the BC dimer interface and inhibit the BC activity by disrupting the oligomerization of this domain. Observations from native gel electrophoresis confirm this structural insight. The structural information provides a foundation for structure-based design of new inhibitors against these enzymes.

PubMed: 15610732
DOI: 10.1016/J.MOLCEL.2004.11.034

Experimental method

X-RAY DIFFRACTION (2.5 Å)