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| | ==Crystal Structure of the humanized carboxyltransferase domain of yeast Acetyl-coA caroxylase in complex with compound 1== | | ==Crystal Structure of the humanized carboxyltransferase domain of yeast Acetyl-coA caroxylase in complex with compound 1== |
| - | <StructureSection load='3tv5' size='340' side='right' caption='[[3tv5]], [[Resolution|resolution]] 2.80Å' scene=''> | + | <StructureSection load='3tv5' size='340' side='right'caption='[[3tv5]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3tv5]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_s288c Saccharomyces cerevisiae s288c]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TV5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TV5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3tv5]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Baker's_yeast Baker's yeast]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TV5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TV5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RCP:(3R)-1-(9-ANTHRYLCARBONYL)-3-(MORPHOLIN-4-YLCARBONYL)-1,4-BIPIPERIDINE'>RCP</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RCP:(3R)-1-(9-ANTHRYLCARBONYL)-3-(MORPHOLIN-4-YLCARBONYL)-1,4-BIPIPERIDINE'>RCP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACC1, ABP2, FAS3, MTR7, YNR016C, N3175 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=559292 Saccharomyces cerevisiae S288c])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACC1, ABP2, FAS3, MTR7, YNR016C, N3175 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=559292 Baker's yeast])</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3tv5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tv5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tv5 RCSB], [http://www.ebi.ac.uk/pdbsum/3tv5 PDBsum]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3tv5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tv5 OCA], [https://pdbe.org/3tv5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tv5 RCSB], [https://www.ebi.ac.uk/pdbsum/3tv5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tv5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ACAC_YEAST ACAC_YEAST]] Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. Involved in the synthesis of very-long-chain fatty acid synthesis which is required to maintain a functional nuclear envelope. Required for acylation and vacuolar membrane association of VAC8 which is necessary to maintain a normal morphology of the vacuole.<ref>PMID:6108218</ref> <ref>PMID:6103540</ref> <ref>PMID:8943372</ref> <ref>PMID:10757783</ref> <ref>PMID:12730220</ref> | + | [[https://www.uniprot.org/uniprot/ACAC_YEAST ACAC_YEAST]] Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. Involved in the synthesis of very-long-chain fatty acid synthesis which is required to maintain a functional nuclear envelope. Required for acylation and vacuolar membrane association of VAC8 which is necessary to maintain a normal morphology of the vacuole.<ref>PMID:6108218</ref> <ref>PMID:6103540</ref> <ref>PMID:8943372</ref> <ref>PMID:10757783</ref> <ref>PMID:12730220</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 3tv5" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Acetyl-CoA carboxylase|Acetyl-CoA carboxylase]] | + | *[[Acetyl-CoA carboxylase 3D structures|Acetyl-CoA carboxylase 3D structures]] |
| - | *[[Biotin carboxylase|Biotin carboxylase]]
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Saccharomyces cerevisiae s288c]] | + | [[Category: Baker's yeast]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Anderson, M D]] | | [[Category: Anderson, M D]] |
| | [[Category: Corbett, J W]] | | [[Category: Corbett, J W]] |
| Structural highlights
3tv5 is a 3 chain structure with sequence from Baker's yeast. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Gene: | ACC1, ABP2, FAS3, MTR7, YNR016C, N3175 (Baker's yeast) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[ACAC_YEAST] Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. Involved in the synthesis of very-long-chain fatty acid synthesis which is required to maintain a functional nuclear envelope. Required for acylation and vacuolar membrane association of VAC8 which is necessary to maintain a normal morphology of the vacuole.[1] [2] [3] [4] [5]
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[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mishina M, Roggenkamp R, Schweizer E. Yeast mutants defective in acetyl-coenzyme A carboxylase and biotin: apocarboxylase ligase. Eur J Biochem. 1980 Oct;111(1):79-87. PMID:6108218
- ↑ Roggenkamp R, Numa S, Schweizer E. Fatty acid-requiring mutant of Saccharomyces cerevisiae defective in acetyl-CoA carboxylase. Proc Natl Acad Sci U S A. 1980 Apr;77(4):1814-7. PMID:6103540
- ↑ Schneiter R, Hitomi M, Ivessa AS, Fasch EV, Kohlwein SD, Tartakoff AM. A yeast acetyl coenzyme A carboxylase mutant links very-long-chain fatty acid synthesis to the structure and function of the nuclear membrane-pore complex. Mol Cell Biol. 1996 Dec;16(12):7161-72. PMID:8943372
- ↑ Schneiter R, Guerra CE, Lampl M, Tatzer V, Zellnig G, Klein HL, Kohlwein SD. A novel cold-sensitive allele of the rate-limiting enzyme of fatty acid synthesis, acetyl coenzyme A carboxylase, affects the morphology of the yeast vacuole through acylation of Vac8p. Mol Cell Biol. 2000 May;20(9):2984-95. PMID:10757783
- ↑ Gao H, Sumanaweera N, Bailer SM, Stochaj U. Nuclear accumulation of the small GTPase Gsp1p depends on nucleoporins Nup133p, Rat2p/Nup120p, Nup85p, Nic96p, and the acetyl-CoA carboxylase Acc1p. J Biol Chem. 2003 Jul 11;278(28):25331-40. Epub 2003 May 1. PMID:12730220 doi:http://dx.doi.org/10.1074/jbc.M301607200
- ↑ Rajamohan F, Marr E, Reyes AR, Landro JA, Anderson MD, Corbett JW, Dirico KJ, Harwood JH, Tu M, Vajdos FF. Structure-guided inhibitor design For human acetyl-coenzyme A charboxylase by interspecies active site conversion. J Biol Chem. 2011 Sep 27. PMID:21953464 doi:10.1074/jbc.M111.275396
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