8SE6

NKG2D complexed with inhibitor 36

8SE6 の概要

• エントリーDOI: 10.2210/pdb8se6/pdb
• 分子名称: NKG2-D type II integral membrane protein, TRIETHYLENE GLYCOL, N-[(1S)-2-(dimethylamino)-2-oxo-1-{3-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]phenyl}ethyl]-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide, ... (5 entities in total)
• 機能のキーワード: nkg2d, del, cryptic pocket, immunoreceptors, immune system, signaling protein, immune system-inhibitor complex, immune system/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31120.12

構造登録者

Thompson, A.A.,Grant, J.C.,Karpowich, N.K.,Sharma, S. (登録日: 2023-04-08, 公開日: 2023-10-11, 最終更新日: 2024-11-20)

主引用文献

Wang, J.,Nakafuku, K.M.,Ziff, J.,Gelin, C.F.,Gholami, H.,Thompson, A.A.,Karpowich, N.K.,Limon, L.,Coate, H.R.,Damm-Ganamet, K.L.,Shih, A.Y.,Grant, J.C.,Cote, M.,Mak, P.A.,Pascual, H.A.,Rives, M.L.,Edwards, J.P.,Venable, J.D.,Venkatesan, H.,Shi, Z.,Allen, S.J.,Sharma, S.,Kung, P.P.,Shireman, B.T.
Development of small molecule inhibitors of natural killer group 2D receptor (NKG2D).
Bioorg.Med.Chem.Lett., 96:129492-129492, 2023

PubMed Abstract: Natural killer group 2D (NKG2D) is a homodimeric activating immunoreceptor whose function is to detect and eliminate compromised cells upon binding to the NKG2D ligands (NKG2DL) major histocompatibility complex (MHC) molecules class I-related chain A (MICA) and B (MICB) and UL16 binding proteins (ULBP1-6). While typically present at low levels in healthy cells and tissue, NKG2DL expression can be induced by viral infection, cellular stress or transformation. Aberrant activity along the NKG2D/NKG2DL axis has been associated with autoimmune diseases due to the increased expression of NKG2D ligands in human disease tissue, making NKG2D inhibitors an attractive target for immunomodulation. Herein we describe the discovery and optimization of small molecule PPI (protein-protein interaction) inhibitors of NKG2D/NKG2DL. Rapid SAR was guided by structure-based drug design and accomplished by iterative singleton and parallel medicinal chemistry synthesis. These efforts resulted in the identification of several potent analogs (14, 21, 30, 45) with functional activity and improved LLE.

PubMed: 37778428
DOI: 10.1016/j.bmcl.2023.129492

実験手法

X-RAY DIFFRACTION (1.36 Å)