6ael | pdb_00006ael
Crystal structure of ENPP1 in complex with 3'3'-cGAMP
Structural highlights
DiseaseENPP1_MOUSE Defects in Enpp1 are the cause of the tiptoe walking (ttw) phenotype. Ttw mice exhibit ossification of the spinal ligaments.[1] FunctionENPP1_MOUSE Appears to modulate insulin sensitivity (By similarity). By generating PPi, plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. PPi inhibits mineralization by binding to nascent hydroxyapatite (HA) crystals, thereby preventing further growth of these crystals. Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates with release of pyrophosphate and diadenosine polyphosphates, and also 3',5'-cAMP to AMP. May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling.[2] [3] Publication Abstract from PubMedENPP1 (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. Structural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 1.,Kato K, Nishimasu H, Oikawa D, Hirano S, Hirano H, Kasuya G, Ishitani R, Tokunaga F, Nureki O Nat Commun. 2018 Oct 24;9(1):4424. doi: 10.1038/s41467-018-06922-7. PMID:30356045[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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