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| | ==Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with compound 7== | | ==Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with compound 7== |
| - | <StructureSection load='3h0s' size='340' side='right' caption='[[3h0s]], [[Resolution|resolution]] 2.43Å' scene=''> | + | <StructureSection load='3h0s' size='340' side='right'caption='[[3h0s]], [[Resolution|resolution]] 2.43Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3h0s]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_18824 Atcc 18824]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H0S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3H0S FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3h0s]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H0S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H0S FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B38:1-(1H-INDAZOL-7-YLCARBONYL)-6-METHYLSPIRO[CHROMENE-2,4-PIPERIDIN]-4(3H)-ONE'>B38</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.43Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3h0j|3h0j]], [[3h0q|3h0q]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B38:1-(1H-INDAZOL-7-YLCARBONYL)-6-METHYLSPIRO[CHROMENE-2,4-PIPERIDIN]-4(3H)-ONE'>B38</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FAS3, ACC1, YNR016C, N3175 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 ATCC 18824])</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=3h0s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h0s OCA], [https://pdbe.org/3h0s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h0s RCSB], [https://www.ebi.ac.uk/pdbsum/3h0s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h0s ProSAT]</span></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=3h0s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h0s OCA], [http://pdbe.org/3h0s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3h0s RCSB], [http://www.ebi.ac.uk/pdbsum/3h0s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3h0s 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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h0/3h0s_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h0/3h0s_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
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| | </div> | | </div> |
| | <div class="pdbe-citations 3h0s" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3h0s" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Acetyl-CoA carboxylase 3D structures|Acetyl-CoA carboxylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Atcc 18824]] | + | [[Category: Large Structures]] |
| - | [[Category: Vajdos, F]] | + | [[Category: Saccharomyces cerevisiae]] |
| - | [[Category: Acc]] | + | [[Category: Vajdos F]] |
| - | [[Category: Acetyl-coa carboxylase]]
| + | |
| - | [[Category: Atp-binding]]
| + | |
| - | [[Category: Biotin]]
| + | |
| - | [[Category: Carboxyltransferase]]
| + | |
| - | [[Category: Ct]]
| + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Fatty acid biosynthesis]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Lipid synthesis]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Multifunctional enzyme]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.
Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2.,Corbett JW, Freeman-Cook KD, Elliott R, Vajdos F, Rajamohan F, Kohls D, Marr E, Zhang H, Tong L, Tu M, Murdande S, Doran SD, Houser JA, Song W, Jones CJ, Coffey SB, Buzon L, Minich ML, Dirico KJ, Tapley S, McPherson RK, Sugarman E, Harwood HJ Jr, Esler W Bioorg Med Chem Lett. 2010 Apr 1;20(7):2383-8. Epub 2009 Apr 24. PMID:20219367[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
- ↑ Corbett JW, Freeman-Cook KD, Elliott R, Vajdos F, Rajamohan F, Kohls D, Marr E, Zhang H, Tong L, Tu M, Murdande S, Doran SD, Houser JA, Song W, Jones CJ, Coffey SB, Buzon L, Minich ML, Dirico KJ, Tapley S, McPherson RK, Sugarman E, Harwood HJ Jr, Esler W. Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2. Bioorg Med Chem Lett. 2010 Apr 1;20(7):2383-8. Epub 2009 Apr 24. PMID:20219367 doi:10.1016/j.bmcl.2009.04.091
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