8Q6F

HUMAN PI4KIIIB IN COMPLEX WITH COVALENTLY BOUND INHIBITOR (COMPOUND 4)

8Q6F の概要

• エントリーDOI: 10.2210/pdb8q6f/pdb
• 分子名称: Phosphatidylinositol 4-kinase beta, 3-(3-fluorosulfonyloxy-4-methoxy-phenyl)-2,5-dimethyl-7-(pyridin-4-ylmethylamino)pyrazolo[1,5-a]pyrimidine, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: lipid kinase, transferase-signaling protein complex, covalent inhibitor., transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 49411.98

構造登録者

Somers, D.O. (登録日: 2023-08-11, 公開日: 2023-12-13, 最終更新日: 2024-11-06)

主引用文献

Cosgrove, B.,Grant, E.K.,Bertrand, S.,Down, K.D.,Somers, D.O.,P Evans, J.,Tomkinson, N.C.O.,Barker, M.D.
Covalent targeting of non-cysteine residues in PI4KIII beta.
Rsc Chem Biol, 4:1111-1122, 2023

PubMed Abstract: The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIβ is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy. Combination of this knowledge showed that a dual covalent inhibitor could be developed which reveals potential in addressing the challenges associated with drug resistant mutations.

PubMed: 38033723
DOI: 10.1039/d3cb00142c

実験手法

X-RAY DIFFRACTION (1.506 Å)