2gp6: Difference between revisions

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New page: left|200px<br /><applet load="2gp6" size="450" color="white" frame="true" align="right" spinBox="true" caption="2gp6, resolution 2.400Å" /> '''X-ray crystal struc...
 
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[[Image:2gp6.gif|left|200px]]<br /><applet load="2gp6" size="450" color="white" frame="true" align="right" spinBox="true"
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'''X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB)'''<br />


==Overview==
==X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB)==
Mycolic acids are long chain alpha-alkyl branched, beta-hydroxy fatty, acids that represent a characteristic component of the Mycobacterium, tuberculosis cell wall. Through their covalent attachment to peptidoglycan, via an arabinogalactan polysaccharide, they provide the basis for an, essential outer envelope membrane. Mycobacteria possess two fatty acid, synthases (FAS); FAS-I carries out de novo synthesis of fatty acids while, FAS-II is considered to elongate medium chain length fatty acyl primers to, provide long chain (C(56)) precursors of mycolic acids. Here we report the, crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier, protein synthase (ACP) II mtKasB, a mycobacterial elongation condensing, enzyme involved in FAS-II. This enzyme, along with the M. tuberculosis, beta-ketoacyl ACP synthase I mtKasA, catalyzes the Claisen-type, condensation reaction responsible for fatty acyl elongation in FAS-II and, are potential targets for development of novel anti-tubercular drugs. The, crystal structure refined to 2.4 A resolution revealed that, like other, KAS-II enzymes, mtKasB adopts a thiolase fold but contains unique, structural features in the capping region that may be crucial to its, preference for longer fatty acyl chains than its counterparts from other, bacteria. Modeling of mtKasA using the mtKasB structure as a template, predicts the overall structures to be almost identical, but a larger, entrance to the active site tunnel is envisaged that might contribute to, the greater sensitivity of mtKasA to the inhibitor thiolactomycin (TLM)., Modeling of TLM binding in mtKasB shows that the drug fits the active site, poorly and results of enzyme inhibition assays using TLM analogues are, wholly consistent with our structural observations. Consequently, the, structure described here further highlights the potential of TLM as an, anti-tubercular lead compound and will aid further exploration of the TLM, scaffold towards the design of novel compounds, which inhibit, mycobacterial KAS enzymes more effectively.
<StructureSection load='2gp6' size='340' side='right'caption='[[2gp6]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2gp6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GP6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GP6 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]] 2.4&#8491;</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=2gp6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gp6 OCA], [https://pdbe.org/2gp6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gp6 RCSB], [https://www.ebi.ac.uk/pdbsum/2gp6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gp6 ProSAT], [https://www.topsan.org/Proteins/TBSGC/2gp6 TOPSAN]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KASB_MYCTU KASB_MYCTU] Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis. Catalyzes the elongation of long chain acyl-ACP substrates by the addition of two carbons from malonyl-ACP to an acyl acceptor (PubMed:11600501, PubMed:12464486, PubMed:16873379). Involved in extension of the mycolate chains to full lengths and produces longer chain multiunsaturated hydrocarbons averaging 54 carbons in length (PubMed:12464486). Essential for resistance to macrophage antimicrobial activity (PubMed:12950920).<ref>PMID:11600501</ref> <ref>PMID:12464486</ref> <ref>PMID:12950920</ref> <ref>PMID:16873379</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/gp/2gp6_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=2gp6 ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
2GP6 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/Beta-ketoacyl-acyl-carrier-protein_synthase_I Beta-ketoacyl-acyl-carrier-protein synthase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.41 2.3.1.41] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2GP6 OCA].
*[[Acyl carrier protein synthase 3D structures|Acyl carrier protein synthase 3D structures]]
 
== References ==
==Reference==
<references/>
X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB)., Sridharan S, Wang L, Brown AK, Dover LG, Kremer L, Besra GS, Sacchettini JC, J Mol Biol. 2007 Feb 16;366(2):469-80. Epub 2006 Nov 7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17174327 17174327]
__TOC__
[[Category: Beta-ketoacyl-acyl-carrier-protein synthase I]]
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Single protein]]
[[Category: Sacchettini J]]
[[Category: Sacchettini, J.]]
[[Category: Sridharan S]]
[[Category: Sridharan, S.]]
[[Category: TBSGC, TB.Structural.Genomics.Consortium.]]
[[Category: protein structure initiative]]
[[Category: psi]]
[[Category: structural genomics]]
[[Category: tb structural genomics consortium]]
[[Category: tbsgc]]
[[Category: thiolase fold]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 11:19:01 2007''

Latest revision as of 12:29, 14 February 2024

X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB)X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB)

Structural highlights

2gp6 is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.4Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT, TOPSAN

Function

KASB_MYCTU Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis. Catalyzes the elongation of long chain acyl-ACP substrates by the addition of two carbons from malonyl-ACP to an acyl acceptor (PubMed:11600501, PubMed:12464486, PubMed:16873379). Involved in extension of the mycolate chains to full lengths and produces longer chain multiunsaturated hydrocarbons averaging 54 carbons in length (PubMed:12464486). Essential for resistance to macrophage antimicrobial activity (PubMed:12950920).[1] [2] [3] [4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Schaeffer ML, Agnihotri G, Volker C, Kallender H, Brennan PJ, Lonsdale JT. Purification and biochemical characterization of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthases KasA and KasB. J Biol Chem. 2001 Dec 14;276(50):47029-37. PMID:11600501 doi:10.1074/jbc.M108903200
  2. ↑ Slayden RA, Barry CE 3rd. The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis. Tuberculosis (Edinb). 2002;82(4-5):149-60. PMID:12464486 doi:10.1054/tube.2002.0333
  3. ↑ Gao LY, Laval F, Lawson EH, Groger RK, Woodruff A, Morisaki JH, Cox JS, Daffe M, Brown EJ. Requirement for kasB in Mycobacterium mycolic acid biosynthesis, cell wall impermeability and intracellular survival: implications for therapy. Mol Microbiol. 2003 Sep;49(6):1547-63. PMID:12950920 doi:10.1046/j.1365-2958.2003.03667.x
  4. ↑ Molle V, Brown AK, Besra GS, Cozzone AJ, Kremer L. The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation. J Biol Chem. 2006 Oct 6;281(40):30094-103. PMID:16873379 doi:10.1074/jbc.M601691200

2gp6, resolution 2.40Å

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