6AEK

Crystal structure of ENPP1 in complex with pApG

Summary for 6AEK

• Entry DOI: 10.2210/pdb6aek/pdb
• Descriptor: Ectonucleotide pyrophosphatase/phosphodiesterase 1, isoform CRA_d, alpha-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, ... (10 entities in total)
• Functional Keywords: enzyme, phoshodiesterase, cgamp, cgas-sting, cyclic gmp-amp, immunosuppressant
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 87532.79

Authors

Kato, K.,Nishimasu, H.,Hirano, S.,Hirano, H.,Ishitani, R.,Nureki, O. (deposition date: 2018-08-05, release date: 2019-03-06, Last modification date: 2024-10-30)

Primary citation

Kato, K.,Nishimasu, H.,Oikawa, D.,Hirano, S.,Hirano, H.,Kasuya, G.,Ishitani, R.,Tokunaga, F.,Nureki, O.
Structural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 1.
Nat Commun, 9:4424-4424, 2018

PubMed Abstract: 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.

PubMed: 30356045
DOI: 10.1038/s41467-018-06922-7

Experimental method

X-RAY DIFFRACTION (1.8 Å)