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==Crystal structure of the Delta-pyrroline-5-carboxylate dehydrogenase from Mycobacterium tuberculosis== | |||
=== | <StructureSection load='4idm' size='340' side='right' caption='[[4idm]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4idm]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IDM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IDM FirstGlance]. <br> | |||
</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ids|4ids]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rv1187 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/1-pyrroline-5-carboxylate_dehydrogenase 1-pyrroline-5-carboxylate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.12 1.5.1.12] </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=4idm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4idm OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4idm RCSB], [http://www.ebi.ac.uk/pdbsum/4idm PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The proline-utilization pathway in Mycobacterium tuberculosis (Mtb) has recently been identified as an important factor in Mtb persistence in vivo, suggesting that this pathway could be a valuable therapeutic target against tuberculosis (TB). In Mtb, two distinct enzymes perform the conversion of proline into glutamate: the first step is the oxidation of proline into Delta(1)-pyrroline-5-carboxylic acid (P5C) by the flavoenzyme proline dehydrogenase (PruB), and the second reaction involves converting the tautomeric form of P5C (glutamate-gamma-semialdehyde) into glutamate using the NAD(+)-dependent Delta(1)-pyrroline-5-carboxylic dehydrogenase (PruA). Here, the three-dimensional structures of Mtb-PruA, determined by X-ray crystallography, in the apo state and in complex with NAD(+) are described at 2.5 and 2.1 A resolution, respectively. The structure reveals a conserved NAD(+)-binding mode, common to other related enzymes. Species-specific conformational differences in the active site, however, linked to changes in the dimer interface, suggest possibilities for selective inhibition of Mtb-PruA despite its reasonably high sequence identity to other PruA enzymes. Using recombinant PruA and PruB, the proline-utilization pathway in Mtb has also been reconstituted in vitro. Functional validation using a novel NMR approach has demonstrated that the PruA and PruB enzymes are together sufficient to convert proline to glutamate, the first such demonstration for monofunctional proline-utilization enzymes. | |||
Characterization of the proline-utilization pathway in Mycobacterium tuberculosis through structural and functional studies.,Lagautriere T, Bashiri G, Paterson NG, Berney M, Cook GM, Baker EN Acta Crystallogr D Biol Crystallogr. 2014 Apr 1;70(Pt 4):968-80. doi:, 10.1107/S1399004713034391. Epub 2014 Mar 19. PMID:24699642<ref>PMID:24699642</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
==See Also== | |||
*[[Pyrroline-5-carboxylate dehydrogenase|Pyrroline-5-carboxylate dehydrogenase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: 1-pyrroline-5-carboxylate dehydrogenase]] | [[Category: 1-pyrroline-5-carboxylate dehydrogenase]] | ||
[[Category: Myctu]] | [[Category: Myctu]] | ||
[[Category: Baker, E N | [[Category: Baker, E N]] | ||
[[Category: Bashiri, G | [[Category: Bashiri, G]] | ||
[[Category: Lagautriere, T | [[Category: Lagautriere, T]] | ||
[[Category: Aldehyde dehydrogenase]] | [[Category: Aldehyde dehydrogenase]] | ||
[[Category: Dehydrogenation]] | [[Category: Dehydrogenation]] | ||
Revision as of 12:57, 25 January 2015
Crystal structure of the Delta-pyrroline-5-carboxylate dehydrogenase from Mycobacterium tuberculosisCrystal structure of the Delta-pyrroline-5-carboxylate dehydrogenase from Mycobacterium tuberculosis
Structural highlights
Publication Abstract from PubMedThe proline-utilization pathway in Mycobacterium tuberculosis (Mtb) has recently been identified as an important factor in Mtb persistence in vivo, suggesting that this pathway could be a valuable therapeutic target against tuberculosis (TB). In Mtb, two distinct enzymes perform the conversion of proline into glutamate: the first step is the oxidation of proline into Delta(1)-pyrroline-5-carboxylic acid (P5C) by the flavoenzyme proline dehydrogenase (PruB), and the second reaction involves converting the tautomeric form of P5C (glutamate-gamma-semialdehyde) into glutamate using the NAD(+)-dependent Delta(1)-pyrroline-5-carboxylic dehydrogenase (PruA). Here, the three-dimensional structures of Mtb-PruA, determined by X-ray crystallography, in the apo state and in complex with NAD(+) are described at 2.5 and 2.1 A resolution, respectively. The structure reveals a conserved NAD(+)-binding mode, common to other related enzymes. Species-specific conformational differences in the active site, however, linked to changes in the dimer interface, suggest possibilities for selective inhibition of Mtb-PruA despite its reasonably high sequence identity to other PruA enzymes. Using recombinant PruA and PruB, the proline-utilization pathway in Mtb has also been reconstituted in vitro. Functional validation using a novel NMR approach has demonstrated that the PruA and PruB enzymes are together sufficient to convert proline to glutamate, the first such demonstration for monofunctional proline-utilization enzymes. Characterization of the proline-utilization pathway in Mycobacterium tuberculosis through structural and functional studies.,Lagautriere T, Bashiri G, Paterson NG, Berney M, Cook GM, Baker EN Acta Crystallogr D Biol Crystallogr. 2014 Apr 1;70(Pt 4):968-80. doi:, 10.1107/S1399004713034391. Epub 2014 Mar 19. PMID:24699642[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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