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| - | [[Image:2ntn.gif|left|200px]]<br /><applet load="2ntn" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2ntn, resolution 2.30Å" /> | |
| - | '''Crystal structure of MabA-C60V/G139A/S144L'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal structure of MabA-C60V/G139A/S144L== |
| - | The MabA protein from Mycobacterium tuberculosis is a validated drug, target. Previous structural studies of this protein showed dynamic, behaviour in the catalytic site and described motion between an open, ;active' holo form (with NADP) and a closed ;inactive' apo form (without, NADP). Here, a mutation (G139A) is reported that leads to complete protein, inactivation and freezes the catalytic site into its closed form, even in, the presence of the cofactor. This observation suggests a new way to, develop anti-MabA drugs via protein stabilization of the ;inactive' form. | + | <StructureSection load='2ntn' size='340' side='right'caption='[[2ntn]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2ntn]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NTN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NTN FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</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=2ntn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ntn OCA], [https://pdbe.org/2ntn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ntn RCSB], [https://www.ebi.ac.uk/pdbsum/2ntn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ntn ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/MABA_MYCTU MABA_MYCTU] Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis (PubMed:11932442). Catalyzes the NADPH-dependent reduction of beta-ketoacyl derivatives, the second step of the FAS-II elongation cycle (PubMed:9802011, PubMed:11932442, PubMed:17059223, PubMed:18155153, PubMed:19685079). May preferentially metabolize long-chain substrates (C8-C20) (PubMed:11932442). Can use CoA derivatives as substrates in vitro (PubMed:9802011, PubMed:11932442, PubMed:17059223, PubMed:18155153).<ref>PMID:11932442</ref> <ref>PMID:17059223</ref> <ref>PMID:18155153</ref> <ref>PMID:19685079</ref> <ref>PMID:9802011</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nt/2ntn_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ntn ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The MabA protein from Mycobacterium tuberculosis is a validated drug target. Previous structural studies of this protein showed dynamic behaviour in the catalytic site and described motion between an open 'active' holo form (with NADP) and a closed 'inactive' apo form (without NADP). Here, a mutation (G139A) is reported that leads to complete protein inactivation and freezes the catalytic site into its closed form, even in the presence of the cofactor. This observation suggests a new way to develop anti-MabA drugs via protein stabilization of the 'inactive' form. |
| | | | |
| - | ==About this Structure==
| + | Lack of dynamics in the MabA active site kills the enzyme activity: practical consequences for drug-design studies.,Poncet-Montange G, Ducasse-Cabanot S, Quemard A, Labesse G, Cohen-Gonsaud M Acta Crystallogr D Biol Crystallogr. 2007 Aug;63(Pt 8):923-5. Epub 2007, Jul 17. PMID:17642518<ref>PMID:17642518</ref> |
| - | 2NTN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Active as [http://en.wikipedia.org/wiki/3-oxoacyl-[acyl-carrier-protein]_reductase 3-oxoacyl-[acyl-carrier-protein] reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.100 1.1.1.100] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NTN OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Lack of dynamics in the MabA active site kills the enzyme activity: practical consequences for drug-design studies., Poncet-Montange G, Ducasse-Cabanot S, Quemard A, Labesse G, Cohen-Gonsaud M, Acta Crystallogr D Biol Crystallogr. 2007 Aug;63(Pt 8):923-5. Epub 2007, Jul 17. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17642518 17642518]
| + | </div> |
| - | [[Category: 3-oxoacyl-[acyl-carrier-protein] reductase]]
| + | <div class="pdbe-citations 2ntn" style="background-color:#fffaf0;"></div> |
| - | [[Category: Mycobacterium tuberculosis]]
| + | |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Cohen-Gonsaud, M.]]
| + | |
| - | [[Category: Ducasse-Cabanot, S.]]
| + | |
| - | [[Category: Labesse, G.]]
| + | |
| - | [[Category: Poncet-Montange, G.]]
| + | |
| - | [[Category: Quemard, A.]]
| + | |
| - | [[Category: beta-ketoacyl acp reductase]]
| + | |
| - | [[Category: inactive]]
| + | |
| - | [[Category: oxidoreductase]]
| + | |
| - | [[Category: sdr]]
| + | |
| | | | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:07:09 2008''
| + | ==See Also== |
| | + | *[[Beta-ketoacyl carrier protein reductase 3D structures|Beta-ketoacyl carrier protein reductase 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| | + | [[Category: Cohen-Gonsaud M]] |
| | + | [[Category: Ducasse-Cabanot S]] |
| | + | [[Category: Labesse G]] |
| | + | [[Category: Poncet-Montange G]] |
| | + | [[Category: Quemard A]] |
| Structural highlights
Function
MABA_MYCTU Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis (PubMed:11932442). Catalyzes the NADPH-dependent reduction of beta-ketoacyl derivatives, the second step of the FAS-II elongation cycle (PubMed:9802011, PubMed:11932442, PubMed:17059223, PubMed:18155153, PubMed:19685079). May preferentially metabolize long-chain substrates (C8-C20) (PubMed:11932442). Can use CoA derivatives as substrates in vitro (PubMed:9802011, PubMed:11932442, PubMed:17059223, PubMed:18155153).[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
The MabA protein from Mycobacterium tuberculosis is a validated drug target. Previous structural studies of this protein showed dynamic behaviour in the catalytic site and described motion between an open 'active' holo form (with NADP) and a closed 'inactive' apo form (without NADP). Here, a mutation (G139A) is reported that leads to complete protein inactivation and freezes the catalytic site into its closed form, even in the presence of the cofactor. This observation suggests a new way to develop anti-MabA drugs via protein stabilization of the 'inactive' form.
Lack of dynamics in the MabA active site kills the enzyme activity: practical consequences for drug-design studies.,Poncet-Montange G, Ducasse-Cabanot S, Quemard A, Labesse G, Cohen-Gonsaud M Acta Crystallogr D Biol Crystallogr. 2007 Aug;63(Pt 8):923-5. Epub 2007, Jul 17. PMID:17642518[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Marrakchi H, Ducasse S, Labesse G, Montrozier H, Margeat E, Emorine L, Charpentier X, Daffe M, Quemard A. MabA (FabG1), a Mycobacterium tuberculosis protein involved in the long-chain fatty acid elongation system FAS-II. Microbiology. 2002 Apr;148(Pt 4):951-60. PMID:11932442
- ↑ Silva RG, de Carvalho LP, Blanchard JS, Santos DS, Basso LA. Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein (ACP) reductase: kinetic and chemical mechanisms. Biochemistry. 2006 Oct 31;45(43):13064-73. PMID:17059223 doi:10.1021/bi0611210
- ↑ Silva RG, Rosado LA, Santos DS, Basso LA. Mycobacterium tuberculosis beta-ketoacyl-ACP reductase: alpha-secondary kinetic isotope effects and kinetic and equilibrium mechanisms of substrate binding. Arch Biochem Biophys. 2008 Mar 1;471(1):1-10. PMID:18155153 doi:10.1016/j.abb.2007.12.002
- ↑ Gurvitz A. The essential mycobacterial genes, fabG1 and fabG4, encode 3-oxoacyl-thioester reductases that are functional in yeast mitochondrial fatty acid synthase type 2. Mol Genet Genomics. 2009 Oct;282(4):407-16. Epub 2009 Aug 14. PMID:19685079 doi:http://dx.doi.org/10.1007/s00438-009-0474-2
- ↑ Banerjee A, Sugantino M, Sacchettini JC, Jacobs WR Jr. The mabA gene from the inhA operon of Mycobacterium tuberculosis encodes a 3-ketoacyl reductase that fails to confer isoniazid resistance. Microbiology. 1998 Oct;144 ( Pt 10):2697-704. PMID:9802011
- ↑ Poncet-Montange G, Ducasse-Cabanot S, Quemard A, Labesse G, Cohen-Gonsaud M. Lack of dynamics in the MabA active site kills the enzyme activity: practical consequences for drug-design studies. Acta Crystallogr D Biol Crystallogr. 2007 Aug;63(Pt 8):923-5. Epub 2007, Jul 17. PMID:17642518 doi:10.1107/S0907444907024158
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