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-Structure paper
Title | Discovery of VH domains that allosterically inhibit ENPP1. |
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Journal, issue, pages | Nat Chem Biol, Vol. 20, Issue 1, Page 30-41, Year 2024 |
Publish date | Jul 3, 2023 |
Authors | Paige E Solomon / Colton J Bracken / Jacqueline A Carozza / Haoqing Wang / Elizabeth P Young / Alon Wellner / Chang C Liu / E Alejandro Sweet-Cordero / Lingyin Li / James A Wells / |
PubMed Abstract | Ectodomain phosphatase/phosphodiesterase-1 (ENPP1) is overexpressed on cancer cells and functions as an innate immune checkpoint by hydrolyzing extracellular cyclic guanosine monophosphate adenosine ...Ectodomain phosphatase/phosphodiesterase-1 (ENPP1) is overexpressed on cancer cells and functions as an innate immune checkpoint by hydrolyzing extracellular cyclic guanosine monophosphate adenosine monophosphate (cGAMP). Biologic inhibitors have not yet been reported and could have substantial therapeutic advantages over current small molecules because they can be recombinantly engineered into multifunctional formats and immunotherapies. Here we used phage and yeast display coupled with in cellulo evolution to generate variable heavy (VH) single-domain antibodies against ENPP1 and discovered a VH domain that allosterically inhibited the hydrolysis of cGAMP and adenosine triphosphate (ATP). We solved a 3.2 Å-resolution cryo-electron microscopy structure for the VH inhibitor complexed with ENPP1 that confirmed its new allosteric binding pose. Finally, we engineered the VH domain into multispecific formats and immunotherapies, including a bispecific fusion with an anti-PD-L1 checkpoint inhibitor that showed potent cellular activity. |
External links | Nat Chem Biol / PubMed:37400538 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.2 Å |
Structure data | EMDB-40047, PDB-8ghr: |
Chemicals | ChemComp-ZN: ChemComp-AMP: ChemComp-NAG: ChemComp-CA: ChemComp-HOH: |
Source |
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Keywords | IMMUNE SYSTEM / phosphodiesterase / inhibitor |