Volume 30, No 1, Jan 2020
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 30 Issue 1, January 2020: 61-69
ORIGINAL ARTICLES
Crystal structure of plant PLDα1 reveals catalytic and regulatory mechanisms of eukaryotic phospholipase D
Jianxu Li1, Fang Yu2, Hui Guo1, Renxue Xiong2, Wenjing Zhang1, Fangyuan He1, Minhua Zhang1 and Peng Zhang 1
1 National Key Laboratory of Plant Molecular Genetics, Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China and 2Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
Correspondence: Peng Zhang (pengzhang01@sibs.ac.cn)These authors contributed equally: Jianxu Li, Fang Yu
Phospholipase D (PLD) hydrolyzes the phosphodiester bond of glycerophospholipids and produces phosphatidic acid (PA), which acts as a second messenger in many living organisms. A large number of PLDs have been identified in eukaryotes, and are viewed as promising targets for drug design because these enzymes are known to be tightly regulated and to function in the pathophysiology of many human diseases. However, the underlying molecular mechanisms of catalysis and regulation of eukaryotic PLD remain elusive. Here, we determined the crystal structure of full-length plant PLDα1 in the apo state and in complex with PA. The structure shows that the N-terminal C2 domain hydrophobically interacts with the C-terminal catalytic domain that features two HKD motifs. Our analysis reveals the catalytic site, substrate-binding mechanism, and a new Ca2+-binding site that is required for the activation of PLD. In addition, we tested several efficient small-molecule inhibitors against PLDα1, and suggested a possible competitive inhibition mechanism according to structure-based docking analysis. This study explains many long-standing questions about PLDs and provides structural insights into PLD-targeted inhibitor/drug design.
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