Szabó, Eszter and Mizsei, Réka and Wilk, P. and Zámbó, Zsófia and Törőcsik, Beáta and Ádám, Veronika and Ambrus, Attila (2018) Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase. FREE RADICAL BIOLOGY AND MEDICINE, 124. pp. 214-220. ISSN 0891-5849
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Abstract
We report the crystal structures of the human (dihydro)lipoamide dehydrogenase (hLADH, hE3) and its disease-causing homodimer interface mutant D444V-hE3 at 2.27 and 1.84 Å resolution, respectively. The wild type structure is a unique uncomplexed, unliganded hE3 structure with the true canonical sequence. Based on the structural information a novel molecular pathomechanism is proposed for the impaired catalytic activity and enhanced capacity for reactive oxygen species generation of the pathogenic mutant. The mechanistic model involves a previously much ignored solvent accessible channel leading to the active site that might be perturbed also by other disease-causing homodimer interface substitutions of this enzyme. © 2018 Elsevier Inc.
Item Type: | Article |
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Uncontrolled Keywords: | OXIDATIVE STRESS; Reactive oxygen species; X-RAY CRYSTALLOGRAPHY; protein structure; Lipoamide Dehydrogenase; Pyruvate Dehydrogenase Complex; Pathogenic mutation; E3 deficiency; Alpha-ketoglutarate dehydrogenase complex; |
Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában > R850-854 Experimental medicine / kisérleti orvostudomány |
SWORD Depositor: | MTMT SWORD |
Depositing User: | MTMT SWORD |
Date Deposited: | 29 Jan 2019 11:00 |
Last Modified: | 29 Jan 2019 11:00 |
URI: | http://real.mtak.hu/id/eprint/90601 |
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