6urf: Difference between revisions
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The | ==Malic enzyme from Mycobacterium tuberculosis== | ||
<StructureSection load='6urf' size='340' side='right'caption='[[6urf]], [[Resolution|resolution]] 3.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6urf]] is a 4 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=6URF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6URF 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]] 3.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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=6urf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6urf OCA], [https://pdbe.org/6urf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6urf RCSB], [https://www.ebi.ac.uk/pdbsum/6urf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6urf ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MAOX_MYCTU MAOX_MYCTU] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Tuberculosis (TB) is the most lethal bacterial infectious disease worldwide. It is notoriously difficult to treat, requiring a cocktail of antibiotics administered over many months. The dense, waxy outer membrane of the TB-causing agent, Mycobacterium tuberculosis (Mtb), acts as a formidable barrier against uptake of antibiotics. Subsequently, enzymes involved in maintaining the integrity of the Mtb cell wall are promising drug targets. Recently, we demonstrated that Mtb lacking malic enzyme (MEZ) has altered cell wall lipid composition and attenuated uptake by macrophages. These results suggest that MEZ contributes to lipid biosynthesis by providing reductants in the form of NAD(P)H. Here, we present the X-ray crystal structure of MEZ to 3.6 A. We use biochemical assays to demonstrate MEZ is dimeric in solution and to evaluate the effects of pH and allosteric regulators on its kinetics and thermal stability. To assess the interactions between MEZ and its substrate malate and cofactors, Mn(2+) and NAD(P)(+), we ran a series of molecular dynamics (MD) simulations. First, the MD analysis corroborates our empirical observations that MEZ is unusually flexible, which persists even with the addition of substrate and cofactors. Second, the MD simulations reveal that dimeric MEZ subunits alternate between open and closed states, and that MEZ can stably bind its NAD(P)(+) cofactor in multiple conformations, including an inactive, compact NAD(+) form. Together the structure of MEZ and insights from its dynamics can be harnessed to inform the design of MEZ inhibitors that target Mtb and not human malic enzyme homologues. | |||
Structural and Molecular Dynamics of Mycobacterium tuberculosis Malic Enzyme, a Potential Anti-TB Drug Target.,Burley KH, Cuthbert BJ, Basu P, Newcombe J, Irimpan EM, Quechol R, Foik IP, Mobley DL, Beste DJV, Goulding CW ACS Infect Dis. 2021 Jan 8;7(1):174-188. doi: 10.1021/acsinfecdis.0c00735. Epub, 2020 Dec 23. PMID:33356117<ref>PMID:33356117</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6urf" style="background-color:#fffaf0;"></div> | ||
[[Category: Burley | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis]] | |||
[[Category: Beste DJ]] | |||
[[Category: Burley KH]] | |||
[[Category: Cuthbert BJ]] | |||
[[Category: Goulding CW]] | |||
[[Category: Mathews EI]] | |||
Latest revision as of 10:56, 11 October 2023
Malic enzyme from Mycobacterium tuberculosisMalic enzyme from Mycobacterium tuberculosis
Structural highlights
FunctionPublication Abstract from PubMedTuberculosis (TB) is the most lethal bacterial infectious disease worldwide. It is notoriously difficult to treat, requiring a cocktail of antibiotics administered over many months. The dense, waxy outer membrane of the TB-causing agent, Mycobacterium tuberculosis (Mtb), acts as a formidable barrier against uptake of antibiotics. Subsequently, enzymes involved in maintaining the integrity of the Mtb cell wall are promising drug targets. Recently, we demonstrated that Mtb lacking malic enzyme (MEZ) has altered cell wall lipid composition and attenuated uptake by macrophages. These results suggest that MEZ contributes to lipid biosynthesis by providing reductants in the form of NAD(P)H. Here, we present the X-ray crystal structure of MEZ to 3.6 A. We use biochemical assays to demonstrate MEZ is dimeric in solution and to evaluate the effects of pH and allosteric regulators on its kinetics and thermal stability. To assess the interactions between MEZ and its substrate malate and cofactors, Mn(2+) and NAD(P)(+), we ran a series of molecular dynamics (MD) simulations. First, the MD analysis corroborates our empirical observations that MEZ is unusually flexible, which persists even with the addition of substrate and cofactors. Second, the MD simulations reveal that dimeric MEZ subunits alternate between open and closed states, and that MEZ can stably bind its NAD(P)(+) cofactor in multiple conformations, including an inactive, compact NAD(+) form. Together the structure of MEZ and insights from its dynamics can be harnessed to inform the design of MEZ inhibitors that target Mtb and not human malic enzyme homologues. Structural and Molecular Dynamics of Mycobacterium tuberculosis Malic Enzyme, a Potential Anti-TB Drug Target.,Burley KH, Cuthbert BJ, Basu P, Newcombe J, Irimpan EM, Quechol R, Foik IP, Mobley DL, Beste DJV, Goulding CW ACS Infect Dis. 2021 Jan 8;7(1):174-188. doi: 10.1021/acsinfecdis.0c00735. Epub, 2020 Dec 23. PMID:33356117[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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