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Crystal structures of human ENPP1 in apo and bound forms
Matthew L Dennis1, Janet Newman1, Olan Dolezal1
1Biomedical Manufacturing Program, CSIRO, 343 Royal Parade, Parkville, VIC 3052, Australia.
Acta Crystallographica. Section D, Structural Biology
|September 3, 2020
Summary
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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