8q6h
HUMAN PI4KIIIB IN COMPLEX WITH COVALENTLY BOUND INHIBITOR (COMPOUND 11)
Structural highlights
FunctionPI4KB_HUMAN Phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate (PIP). May regulate Golgi disintegration/reorganization during mitosis, possibly via its phosphorylation. Involved in Golgi-to-plasma membrane trafficking (By similarity).[1] [2] [3] Publication Abstract from PubMedThe synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIbeta 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. Covalent targeting of non-cysteine residues in PI4KIIIbeta.,Cosgrove B, Grant EK, Bertrand S, Down KD, Somers DO, P Evans J, Tomkinson NCO, Barker MD RSC Chem Biol. 2023 Oct 17;4(12):1111-1122. doi: 10.1039/d3cb00142c. eCollection , 2023 Nov 29. PMID:38033723[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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