6urf | pdb_00006urf

Malic enzyme from Mycobacterium tuberculosis

spinqualitylabelsall models 6urf, resolution 3.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6urf is a 4 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL Gene: mez, mez_2, DSI35_04950, ERS007657_00054, ERS007661_01303, ERS007665_00385, ERS007670_00245, ERS007672_00340, ERS007681_00703, ERS007703_00793, ERS007720_02108, ERS007722_00150, ERS007741_00458, ERS023446_00378, ERS024276_00123, ERS027644_00794, ERS027646_00126, ERS027651_00016, ERS027652_00738, ERS027654_00055, ERS027659_00902, ERS027661_00290, ERS027666_00475, ERS031537_00346, ERS124361_01639, FDK60_04380, SAMEA2682835_05736, SAMEA2682864_03296, SAMEA2683035_01163 ("Bacillus tuberculosis" (Zopf 1883) Klein 1884) Activity: Malate dehydrogenase (oxaloacetate-decarboxylating), with EC number 1.1.1.38 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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