Crystal structures of human ENPP1 in apo and bound forms
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Updated: Dec 10, 2025
Production, Crystallization and Structure Determination of C. difficile PPEP-1 via Microseeding and Zinc-SAD
Published on: December 30, 2016
Matthew L Dennis1, Janet Newman1, Olan Dolezal1
1Biomedical Manufacturing Program, CSIRO, 343 Royal Parade, Parkville, VIC 3052, Australia.
Abstract:
Cancer is one of the leading causes of mortality in humans, and recent work has focused on the area of immuno-oncology, in which the immune system is used to specifically target cancerous cells. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an emerging therapeutic target in human cancers owing to its role in degrading cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING). The available structures of ENPP1 are of the mouse enzyme, and no structures are available with anything other than native nucleotides. Here, the first X-ray crystal structures of the human ENPP1 enzyme in an apo form, with bound nucleotides and with two known inhibitors are presented. The availability of these structures and a robust crystallization system will allow the development of structure-based drug-design campaigns against this attractive cancer therapeutic target.
Insights
Researchers have determined the first X-ray crystal structures of human Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). These structures, including bound inhibitors, pave the way for developing new cancer therapeutics targeting ENPP1.
Area of Science:
- Biochemistry
- Structural Biology
- Cancer Research
Background:
- Cancer remains a leading cause of human mortality.
- Immuno-oncology utilizes the immune system to target cancer cells.
- Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is a key enzyme in cancer, degrading cyclic GMP-AMP (cGAMP), which activates the STING pathway.
Purpose of the Study:
- To determine the first X-ray crystal structures of human ENPP1.
- To provide structural insights into ENPP1 in various states, including apo, bound to nucleotides, and with inhibitors.
- To facilitate structure-based drug design for cancer therapeutics targeting ENPP1.
Main Methods:
- X-ray crystallography was employed to determine the structures of human ENPP1.
- The enzyme was studied in its apo form, with bound nucleotides, and in complex with two known inhibitors.
Main Results:
- The first X-ray crystal structures of human ENPP1 were successfully obtained.
- Structures were determined for the apo enzyme, enzyme with bound nucleotides, and enzyme with two inhibitors.
- A robust crystallization system for human ENPP1 was established.
Conclusions:
- The presented structures offer crucial insights into human ENPP1 function.
- These structural data are vital for advancing structure-based drug design for ENPP1 inhibitors.
- The findings support the development of novel immuno-oncology cancer therapeutics targeting ENPP1.
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