6ohr
Structure of compound 5 bound human Phospholipase D1 catalytic domainStructure of compound 5 bound human Phospholipase D1 catalytic domain
Structural highlights
DiseasePLD1_HUMAN The disease is caused by mutations affecting the gene represented in this entry. FunctionPLD1_HUMAN Implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. May be involved in the regulation of perinuclear intravesicular membrane traffic (By similarity). Publication Abstract from PubMedPhospholipase D enzymes (PLDs) are ubiquitous phosphodiesterases that produce phosphatidic acid (PA), a key second messenger and biosynthetic building block. Although an orthologous bacterial Streptomyces sp. strain PMF PLD structure was solved two decades ago, the molecular basis underlying the functions of the human PLD enzymes (hPLD) remained unclear based on this structure due to the low homology between these sequences. Here, we describe the first crystal structures of hPLD1 and hPLD2 catalytic domains and identify novel structural elements and functional differences between the prokaryotic and eukaryotic enzymes. Furthermore, structure-based mutation studies and structures of inhibitor-hPLD complexes allowed us to elucidate the binding modes of dual and isoform-selective inhibitors, highlight key determinants of isoenzyme selectivity and provide a basis for further structure-based drug discovery and functional characterization of this therapeutically important superfamily of enzymes. Human PLD structures enable drug design and characterization of isoenzyme selectivity.,Metrick CM, Peterson EA, Santoro JC, Enyedy IJ, Murugan P, Chen T, Michelsen K, Cullivan M, Spilker KA, Kumar PR, May-Dracka TL, Chodaparambil JV Nat Chem Biol. 2020 Feb 10. pii: 10.1038/s41589-019-0458-4. doi:, 10.1038/s41589-019-0458-4. PMID:32042197[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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