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PDBsum entry 2onn

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Oxidoreductase PDB id
2onn
Jmol
Contents
Protein chain
(+ 2 more) 494 a.a.
Waters ×737

References listed in PDB file
Key reference
Title Structural and functional consequences of coenzyme binding to the inactive asian variant of mitochondrial aldehyde dehydrogenase: roles of residues 475 and 487.
Authors H.N.Larson, J.Zhou, Z.Chen, J.S.Stamler, H.Weiner, T.D.Hurley.
Ref. J Biol Chem, 2007, 282, 12940-12950. [DOI no: 10.1074/jbc.M607959200]
PubMed id 17327228
Abstract
The common mitochondrial aldehyde dehydrogenase (ALDH2) ALDH2(*)2 polymorphism is associated with impaired ethanol metabolism and decreased efficacy of nitroglycerin treatment. These physiological effects are due to the substitution of Lys for Glu-487 that reduces the k(cat) for these processes and increases the K(m) for NAD(+), as compared with ALDH2. In this study, we sought to understand the nature of the interactions that give rise to the loss of structural integrity and low activity in ALDH2(*)2 even when complexed with coenzyme. Consequently, we have solved the crystal structure of ALDH2(*)2 complexed with coenzyme to 2.5A(.) We have also solved the structures of a mutated form of ALDH2 where Arg-475 is replaced by Gln (R475Q). The structural and functional properties of the R475Q enzyme are intermediate between those of wild-type and the ALDH2(*)2 enzymes. In both cases, the binding of coenzyme restores most of the structural deficits observed in the apoenzyme structures. The binding of coenzyme to the R475Q enzyme restores its structure and catalytic properties to near wild-type levels. In contrast, the disordered helix within the coenzyme binding pocket of ALDH2(*)2 is reordered, but the active site is only partially reordered. Consistent with the structural data, ALDH2(*)2 showed a concentration-dependent increase in esterase activity and nitroglycerin reductase activity upon addition of coenzyme, but the levels of activity do not approach those of the wild-type enzyme or that of the R475Q enzyme. The data presented shows that Glu-487 maintains a critical function in linking the structure of the coenzyme-binding site to that of the active site through its interactions with Arg-264 and Arg-475, and in doing so, creates the stable structural scaffold conducive to catalysis.
Figure 1.
FIGURE 1. Structures of ALDH2^*2. a, subunits C (dark gray) and D (blue) of the apoenzyme ALDH2^*2 structure (PDB ID 1ZUM) which lack ordered G helices. b, subunits A and B of the coenzyme-bound ALDH2^*2 structure with the G helices colored red. The bound coenzyme molecules are represented using space-filling atoms. The ordered portion of the NAD^+ molecule in subunit A, modeled as ADP, is shown in yellow, and the bound NAD^+ molecule in subunit B is shown in gold. All figures for publication were created using either the PyMol Molecular Graphics program (34) or Deep View Swiss PDB Viewer (35) and Pov-Ray (36).
Figure 9.
FIGURE 9. The interactions across the dimer interface contributed by residues 463-478. The structure of the wild-type ALDH2 enzyme with coenzyme-bound (PDB code 1O02) is used for this representation. Subunits A (blue) and B (violet) are shown. a, the loop comprised of residues 463-478 is shown in red for both subunits with the side chain for residue 475 colored according to its subunit. Hydrogen bonds are represented by green dashed lines. b, contacts among residues 463-478, the G helices, and -strands at the interface. The view in this panel is rotated 90° about a horizontal axis with respect to a. The elements of secondary structure are labeled. Residues 246 and 261, which mark the beginning and end of G, are labeled as is residue 470 within the loop that contacts these regions. The bound coenzyme molecules are shown using space-filling atoms and are colored gold.
The above figures are reprinted from an Open Access publication published by the ASBMB: J Biol Chem (2007, 282, 12940-12950) copyright 2007.
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