Structural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 1

Nat Commun. 2018 Oct 24;9(1):4424. doi: 10.1038/s41467-018-06922-7.


ENPP1 (Ecto-nucleotide pyrophosphatase phosphodiesterase 1), a type II transmembrane glycoprotein, hydrolyzes ATP to produce AMP and diphosphate, thereby inhibiting bone mineralization. A recent study showed that ENPP1 also preferentially hydrolyzes 2'3'-cGAMP (cyclic GMP-AMP) but not its linkage isomer 3'3'-cGAMP, and negatively regulates the cGAS-STING pathway in the innate immune system. Here, we present the high-resolution crystal structures of ENPP1 in complex with 3'3'-cGAMP and the reaction intermediate pA(3',5')pG. The structures revealed that the adenine and guanine bases of the dinucleotides are recognized by nucleotide- and guanine-pockets, respectively. Furthermore, the structures indicate that 2'3'-cGAMP, but not 3'3'-cGAMP, binds to the active site in a conformation suitable for catalysis, thereby explaining the specific degradation of 2'3'-cGAMP by ENPP1. Our findings provide insights into how ENPP1 hydrolyzes both ATP and cGAMP to participate in the two distinct biological processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Catalysis
  • Cell Line
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Membrane Proteins / metabolism
  • Nucleotides, Cyclic / chemistry*
  • Nucleotides, Cyclic / metabolism*
  • Phosphoric Diester Hydrolases / chemistry
  • Phosphoric Diester Hydrolases / metabolism*
  • Protein Structure, Secondary
  • Pyrophosphatases / chemistry
  • Pyrophosphatases / metabolism*
  • Signal Transduction / physiology


  • Membrane Proteins
  • Nucleotides, Cyclic
  • STING1 protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Adenosine Triphosphate
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases