3tz3 | pdb_00003tz3

Crystal Structure of the humanized carboxyltransferase domain of yeast Acetyl-coA caroxylase in complex with compound 2

spinqualitylabelsall models 3tz3, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3tz3 is a 3 chain structure with sequence from Saccharomyces cerevisiae s288c. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: B36 Gene: ACC1, ABP2, FAS3, MTR7, YNR016C, N3175 (Saccharomyces cerevisiae S288c) Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed Inhibition of Acetyl-CoA carboxylases (ACCs), a crucial enzyme for fatty acid metabolism, has been shown to promote fatty acid oxidation and reduce body fat in animal models. Therefore, ACCs are attractive targets for structure-based inhibitor design, particularly the carboxyltransferase (CT) domain which is the primary site for inhibitor interaction. We have cloned, expressed and purified the CT domain of human ACC2 using baculovirus mediated insect cell expression system. However, attempts to crystallize the human ACC2 CT domain have not been successful in our hands. Hence, we have been using the available crystal structure of yeast CT domain to design human ACC inhibitors. Unfortunately, as the selectivity of the lead series has increased against the full length human enzyme, the potency against the yeast enzyme has decreased significantly. This loss of potency against the yeast enzyme correlated with a complete lack of binding of the human specific compounds to crystals of the yeast CT domain. Here, we address this problem by converting nine key active site residues of yeast CT domain to the corresponding human residues. The resulting humanized yeast ACC-CT (yCT-H9) protein exhibits biochemical and biophysical properties closer to human CT domain and binding to human specific compounds. We report high resolution crystal structures of yCT-H9 complexed with inhibitors that show a preference for the human CT domain. These structures offer insights which explain the species selectivity of ACC inhibitors and may guide future drug design programs. Structure-guided inhibitor design For human acetyl-coenzyme A charboxylase by interspecies active site conversion.,Rajamohan F, Marr E, Reyes AR, Landro JA, Anderson MD, Corbett JW, Dirico KJ, Harwood JH, Tu M, Vajdos FF J Biol Chem. 2011 Sep 27. PMID:21953464 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acetyl-CoA carboxylase Biotin carboxylase

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