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Publication Abstract from PubMed

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, gammadelta(+), and CD8(+) T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.

Identification of small-molecule protein-protein interaction inhibitors for NKG2D.,Thompson AA, Harbut MB, Kung PP, Karpowich NK, Branson JD, Grant JC, Hagan D, Pascual HA, Bai G, Zavareh RB, Coate HR, Collins BC, Cote M, Gelin CF, Damm-Ganamet KL, Gholami H, Huff AR, Limon L, Lumb KJ, Mak PA, Nakafuku KM, Price EV, Shih AY, Tootoonchi M, Vellore NA, Wang J, Wei N, Ziff J, Berger SB, Edwards JP, Gardet A, Sun S, Towne JE, Venable JD, Shi Z, Venkatesan H, Rives ML, Sharma S, Shireman BT, Allen SJ Proc Natl Acad Sci U S A. 2023 May 2;120(18):e2216342120. doi: , 10.1073/pnas.2216342120. Epub 2023 Apr 25. PMID:37098070^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.