8V05

Crystal structure of mouse PLD3

Summary for 8V05

• Entry DOI: 10.2210/pdb8v05/pdb
• Descriptor: 5'-3' exonuclease PLD3, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: pld3, phospholipase, phosphohistidine, nuclease, hydrolase
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 1
• Total formula weight: 54618.73

Authors

Yuan, M.,Zhu, X.,Wilson, I.A. (deposition date: 2023-11-17, release date: 2024-03-13, Last modification date: 2024-10-30)

Primary citation

Yuan, M.,Peng, L.,Huang, D.,Gavin, A.,Luan, F.,Tran, J.,Feng, Z.,Zhu, X.,Matteson, J.,Wilson, I.A.,Nemazee, D.
Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4.
Structure, 32:766-779.e7, 2024

PubMed Abstract: Endolysosomal exonucleases PLD3 and PLD4 (phospholipases D3 and D4) are associated with autoinflammatory and autoimmune diseases. We report structures of these enzymes, and the molecular basis of their catalysis. The structures reveal an intra-chain dimer topology forming a basic active site at the interface. Like other PLD superfamily members, PLD3 and PLD4 carry HxKxxxxD/E motifs and participate in phosphodiester-bond cleavage. The enzymes digest ssDNA and ssRNA in a 5'-to-3' manner and are blocked by 5'-phosphorylation. We captured structures in apo, intermediate, and product states and revealed a "link-and-release" two-step catalysis. We also unexpectedly demonstrated phosphatase activity via a covalent 3-phosphohistidine intermediate. PLD4 contains an extra hydrophobic clamp that stabilizes substrate and could affect oligonucleotide substrate preference and product release. Biochemical and structural analysis of disease-associated mutants of PLD3/4 demonstrated reduced enzyme activity or thermostability and the possible basis for disease association. Furthermore, these findings provide insight into therapeutic design.

PubMed: 38537643
DOI: 10.1016/j.str.2024.02.019

Experimental method

X-RAY DIFFRACTION (2.08 Å)