6ael

Crystal structure of ENPP1 in complex with 3'3'-cGAMPCrystal structure of ENPP1 in complex with 3'3'-cGAMP

Structural highlights

6ael is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:	, , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ENPP1_MOUSE Defects in Enpp1 are the cause of the tiptoe walking (ttw) phenotype. Ttw mice exhibit ossification of the spinal ligaments.^[1]

Function

ENPP1_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 PubMed

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.

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.

References

↑ Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998 Jul;19(3):271-3. PMID:9662402 doi:http://dx.doi.org/10.1038/956
↑ Rebbe NF, Tong BD, Finley EM, Hickman S. Identification of nucleotide pyrophosphatase/alkaline phosphodiesterase I activity associated with the mouse plasma cell differentiation antigen PC-1. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5192-6. PMID:1647027
↑ Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998 Jul;19(3):271-3. PMID:9662402 doi:http://dx.doi.org/10.1038/956
↑ 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. 2018 Oct 24;9(1):4424. doi: 10.1038/s41467-018-06922-7. PMID:30356045 doi:http://dx.doi.org/10.1038/s41467-018-06922-7

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OCA

[1] Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998 Jul;19(3):271-3. PMID:9662402 doi:http://dx.doi.org/10.1038/956

[2] Rebbe NF, Tong BD, Finley EM, Hickman S. Identification of nucleotide pyrophosphatase/alkaline phosphodiesterase I activity associated with the mouse plasma cell differentiation antigen PC-1. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5192-6. PMID:1647027

[3] Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998 Jul;19(3):271-3. PMID:9662402 doi:http://dx.doi.org/10.1038/956

[4] 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. 2018 Oct 24;9(1):4424. doi: 10.1038/s41467-018-06922-7. PMID:30356045 doi:http://dx.doi.org/10.1038/s41467-018-06922-7

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6ael

Crystal structure of ENPP1 in complex with 3'3'-cGAMPCrystal structure of ENPP1 in complex with 3'3'-cGAMP

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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6ael

Crystal structure of ENPP1 in complex with 3'3'-cGAMPCrystal structure of ENPP1 in complex with 3'3'-cGAMP

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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