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==Crystal Structure of Mycobacterium tuberculosis MenB in Complex with Acetoacetyl-Coenzyme A, a Key Enzyme in Vitamin K2 Biosynthesis== | |||
<StructureSection load='1q51' size='340' side='right'caption='[[1q51]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1q51]] is a 12 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=1Q51 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Q51 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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAA:ACETOACETYL-COENZYME+A'>CAA</scene></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=1q51 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1q51 OCA], [https://pdbe.org/1q51 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1q51 RCSB], [https://www.ebi.ac.uk/pdbsum/1q51 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1q51 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MENB_MYCTU MENB_MYCTU] Converts o-succinylbenzoyl-CoA (OSB-CoA) to 1,4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA).<ref>PMID:12909628</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/q5/1q51_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=1q51 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Bacterial enzymes of the menaquinone (Vitamin K2) pathway are potential drug targets because they lack human homologs. MenB, 1,4-dihydroxy-2-naphthoyl-CoA synthase, the fourth enzyme in the biosynthetic pathway leading from chorismate to menaquinone, catalyzes the conversion of O-succinylbenzoyl-CoA (OSB-CoA) to 1,4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA). Based on our interest in developing novel tuberculosis chemotherapeutics, we have solved the structures of MenB from Mycobacterium tuberculosis and its complex with acetoacetyl-coenzyme A at 1.8 and 2.3 A resolution, respectively. Like other members of the crotonase superfamily, MenB folds as an (alpha3)2 hexamer, but its fold is distinct in that the C terminus crosses the trimer-trimer interface, forming a flexible part of the active site within the opposing trimer. The highly conserved active site of MenB contains a deep pocket lined by Asp-192, Tyr-287, and hydrophobic residues. Mutagenesis shows that Asp-192 and Tyr-287 are essential for enzymatic catalysis. We postulate a catalytic mechanism in which MenB enables proton transfer within the substrate to yield an oxyanion as the initial step in catalysis. Knowledge of the active site geometry and characterization of the catalytic mechanism of MenB will aid in identifying new inhibitors for this potential drug target. | Bacterial enzymes of the menaquinone (Vitamin K2) pathway are potential drug targets because they lack human homologs. MenB, 1,4-dihydroxy-2-naphthoyl-CoA synthase, the fourth enzyme in the biosynthetic pathway leading from chorismate to menaquinone, catalyzes the conversion of O-succinylbenzoyl-CoA (OSB-CoA) to 1,4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA). Based on our interest in developing novel tuberculosis chemotherapeutics, we have solved the structures of MenB from Mycobacterium tuberculosis and its complex with acetoacetyl-coenzyme A at 1.8 and 2.3 A resolution, respectively. Like other members of the crotonase superfamily, MenB folds as an (alpha3)2 hexamer, but its fold is distinct in that the C terminus crosses the trimer-trimer interface, forming a flexible part of the active site within the opposing trimer. The highly conserved active site of MenB contains a deep pocket lined by Asp-192, Tyr-287, and hydrophobic residues. Mutagenesis shows that Asp-192 and Tyr-287 are essential for enzymatic catalysis. We postulate a catalytic mechanism in which MenB enables proton transfer within the substrate to yield an oxyanion as the initial step in catalysis. Knowledge of the active site geometry and characterization of the catalytic mechanism of MenB will aid in identifying new inhibitors for this potential drug target. | ||
Crystal structure of Mycobacterium tuberculosis MenB, a key enzyme in vitamin K2 biosynthesis.,Truglio JJ, Theis K, Feng Y, Gajda R, Machutta C, Tonge PJ, Kisker C J Biol Chem. 2003 Oct 24;278(43):42352-60. Epub 2003 Aug 8. PMID:12909628<ref>PMID:12909628</ref> | |||
Crystal structure of Mycobacterium tuberculosis MenB, a key enzyme in vitamin K2 biosynthesis., Truglio JJ, Theis K, Feng Y, Gajda R, Machutta C, Tonge PJ, Kisker C | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1q51" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis H37Rv]] | |||
[[Category: Feng Y]] | |||
[[Category: Gajda R]] | |||
[[Category: Kisker C]] | |||
[[Category: Machutta C]] | |||
[[Category: Theis K]] | |||
[[Category: Tonge PJ]] | |||
[[Category: Truglio JJ]] | |||
Latest revision as of 12:57, 16 August 2023
Crystal Structure of Mycobacterium tuberculosis MenB in Complex with Acetoacetyl-Coenzyme A, a Key Enzyme in Vitamin K2 BiosynthesisCrystal Structure of Mycobacterium tuberculosis MenB in Complex with Acetoacetyl-Coenzyme A, a Key Enzyme in Vitamin K2 Biosynthesis
Structural highlights
FunctionMENB_MYCTU Converts o-succinylbenzoyl-CoA (OSB-CoA) to 1,4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA).[1] 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 PubMedBacterial enzymes of the menaquinone (Vitamin K2) pathway are potential drug targets because they lack human homologs. MenB, 1,4-dihydroxy-2-naphthoyl-CoA synthase, the fourth enzyme in the biosynthetic pathway leading from chorismate to menaquinone, catalyzes the conversion of O-succinylbenzoyl-CoA (OSB-CoA) to 1,4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA). Based on our interest in developing novel tuberculosis chemotherapeutics, we have solved the structures of MenB from Mycobacterium tuberculosis and its complex with acetoacetyl-coenzyme A at 1.8 and 2.3 A resolution, respectively. Like other members of the crotonase superfamily, MenB folds as an (alpha3)2 hexamer, but its fold is distinct in that the C terminus crosses the trimer-trimer interface, forming a flexible part of the active site within the opposing trimer. The highly conserved active site of MenB contains a deep pocket lined by Asp-192, Tyr-287, and hydrophobic residues. Mutagenesis shows that Asp-192 and Tyr-287 are essential for enzymatic catalysis. We postulate a catalytic mechanism in which MenB enables proton transfer within the substrate to yield an oxyanion as the initial step in catalysis. Knowledge of the active site geometry and characterization of the catalytic mechanism of MenB will aid in identifying new inhibitors for this potential drug target. Crystal structure of Mycobacterium tuberculosis MenB, a key enzyme in vitamin K2 biosynthesis.,Truglio JJ, Theis K, Feng Y, Gajda R, Machutta C, Tonge PJ, Kisker C J Biol Chem. 2003 Oct 24;278(43):42352-60. Epub 2003 Aug 8. PMID:12909628[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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