9b98
From Proteopedia
Crystal structure of the human PAD2 protein bound to small molecule
Structural highlights
FunctionPADI2_HUMAN Catalyzes the deimination of arginine residues of proteins. Publication Abstract from PubMedPeptidyl arginine deiminases (PADs) are important enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, with selectivity over PAD3 and PAD4, from a DNA-encoded library. The biochemical and biophysical characterization of this inhibitor and two noninhibitory binders indicated a novel, Ca(2+) competitive mechanism of inhibition. This was confirmed via X-ray crystallographic analysis. Finally, we demonstrate that this inhibitor selectively inhibits PAD2 in a cellular context. Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism.,Byrnes LJ, Choi WY, Balbo P, Banker ME, Chang J, Chen S, Cheng X, Cong Y, Culp J, Di H, Griffor M, Hall J, Meng X, Morgan B, Mousseau JJ, Nicki J, O'Connell T, Ramsey S, Shaginian A, Shanker S, Trujillo J, Wan J, Vincent F, Wright SW, Vajdos F ACS Chem Biol. 2024 Sep 24. doi: 10.1021/acschembio.4c00397. PMID:39316753[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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